Nitrogen-containing aromatic derivatives

ABSTRACT

A compound represented by the general formula: 
                         
wherein X 1  represents a nitrogen atom or a group represented by the formula —CR 10 ═; X 2  represents a nitrogen atom or a group represented by the formula —CR 11 ═; Y represents an oxygen atom or the like; R 1  represents a C 1-6  alkoxy group, an optionally substituted C 6-10  aryloxy group, a group represented by the formula —NR 12a R 12b  or the like; R 2  represents a hydrogen atom, an optionally substituted C 1-6  alkyl group, or the like; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10  and R 11  each independently represent a hydrogen atom, a halogen atom, an optionally substituted C 1-6  alkyl group, or the like; R 9  represents a group represented by the formula —NR 16a R 16b  or the like; and R 12a , R 12b , R 16a  and R 16b  each independently represent a hydrogen atom, an optionally substituted C 1-6  alkyl group, or the like,
 
a salt thereof, or a hydrate of the foregoing.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/651,496, filed Aug. 29, 2003, now U.S. Pat. No. 7,109,219 whichclaims the benefit of U.S. provisional patent application 60/464,690,filed Apr. 22, 2003, and Japanese Patent Application No. 2002-253123,filed Aug. 30, 2002, the entirety of each of which is herebyincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds effective forprevention and treatment of various diseases associated with abnormalangiogenesis, and to the medical compositions such as angiogenesisinhibitors and antitumor agents containing the novel compounds.

2. Related Background of the Invention

Angiogenesis is an essential biological phenomenon for fetal vascularformation and morphological and functional development of organs. Newblood vessels are assembled through several processes includingendothelial cell migration, proliferation and tube formation, and theparticipation of mast cells, lymphocytes, interstitial cells and thelike has been shown to be important in this process (non-patentliterature 1).

A multiple in vivo angiogenesis-stimulating factors have beenidentified, particularly Vascular Endothelial Growth Factor (hereinafterabbreviated as “VEGF”) and Fibroblast Growth Factor (hereinafterabbreviated as “FGF”) are reported to enhance angiogenesis (non-patentliterature 2 and 3).

Although physiological angiogenesis occurs at the time of healing ofwound or in a female estrous cycle in adult individuals, it is knownthat pathological increase in angiogenesis in adult individuals isinvolved in onset or progression of various disease. Specific diseasesassociated with abnormal angiogenesis include cancer, rheumatoidarthritis, atherosclerosis, diabetic retinopathy, angioma, psoriasis,and the like (non-patent literature 4). In particular, a literature hasindicated angiogenesis dependency for solid tumor growth, andangiogenesis inhibitors are therefore promising as new therapeuticagents for intractable solid tumors (non-patent literature 5).

Patent literature 1 and 2 are provided as prior arts with regard to6-membered nitrogen-containing aromatic derivatives bonded withsubstituted indole.

Although patent literature 1 describes indole derivatives which suppressVEGF-stimulated angiogenesis based on a selective tyrosine kinaseinhibition, the pharmacological test results on their inhibition actionare not disclosed. Although patent literature 2 describes pyridinederivatives bonded with indole ring via an oxygen atom at the4-position, neither the compound according to the present invention northeir inhibiting actions on FGF-stimulated angiogenesis are disclosed.

-   [patent literature 1] WO 02/16348-   [patent literature 2] WO 02/32872-   [non-patent literature 1] J. Biol. Chem., 267, 10931, 1992.-   [non-patent literature 2] Endocrinology, 133, 848, 1993.-   [non-patent literature 3] Biochem. Biophys. Res. Commun., 147, 876,    1987.-   [non-patent literature 4] N. Engl. J. Med., 333, 1757, 1995.-   [non-patent literature 5] J. Natl. Cancer Inst., 82, 4, 1990.

SUMMARY OF THE INVENTION

It is an object of the present invention to investigate and discoverangiogenesis-inhibiting compounds which: (1) exhibit antitumor activityby strongly suppressing both of angiogenesis included by VEGF and FGFwhich are major in vivo angiogenesis factors, (2) are highly useful asdrug materials in terms of their properties, biokinetics and safety, and(3) are useful for amelioration, prevention and treatment of variousdiseases associated with abnormal increase in angiogenesis.

As a result of much diligent research in light of the circumstancesdescribed above, the present inventors have succeeded in synthesizingnovel pyridine derivatives and pyrimidine derivatives represented by thefollowing general formula (I), salts thereof, or hydrates of theforegoing. At the same time, the inventors have completed the presentinvention upon discovering that these compounds, the salts thereof, orthe hydrates of the foregoing exhibit an excellentangiogenesis-inhibiting effect.

Specifically, the present invention provides the followings:

<1> a compound represented by the general formula:

wherein X₁ represents a nitrogen atom or a group represented by theformula —CR₁₀═, X₂ represents a nitrogen atom or a group represented bythe formula —CR₁₁═, and X₁ and X₂ do not represent a nitrogen atom atthe same time;

-   Y represents an oxygen atom, a sulfur atom, a sulfinyl group, a    sulfonyl group, or a group represented by the formula —NR_(Y)—    (wherein R_(Y) represents a hydrogen atom or a C₁₋₆ alkyl group);-   R₁ represents an optionally substituted C₁₋₆ alkoxy group, an    optionally substituted C₆₋₁₀ aryloxy group, a group represented by    the formula —NR_(12a)R_(12b), a group represented by the formula:

(wherein Y_(A1), and Y_(A2) each independently represent a grouprepresented by the formula -A₁₀-A₁₁-A₁₂ (wherein A₁₀ represents a singlebond or an optionally substituted C1-6 alkylene; A₁₁ represents a singlebond, an oxygen atom, a carbonyl group or a sulfonyl group; and A₁₂represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a 5- to10-membered heteroaryl group, a group represented by the formula—NR_(A10)R_(A11), a group represented by the formula —OR_(A12) (whereinR_(A10), R_(A11) and R_(A12) each independently represent a hydrogenatom, a C₁₋₆ alkyl group or C₃₋₈ cycloalkyl group) or a grouprepresented by the formula:

(wherein e represents 1 or 2; Z represents an oxygen atom, a grouprepresented by the formula —CR_(X7)R_(X8)— or a group represented by theformula —NR_(X9)—; R_(X7), R_(X8) and R_(X9) each independentlyrepresent a hydrogen atom, a hydroxyl group or a C₁₋₆ alkyl group)); andY_(A3) represents a hydrogen atom or an optionally substituted C₁₋₆alkyl group) or a group represented by the formula:

(wherein T1 represents an optionally substituted 5- to 10-memberedaromatic heterocycle which may have X in the ring or an optionallysubstituted 3- to 10-membered heterocycle which may have X in the ring);R₃, R₄, R₅, R₆, R₇, R₈, R₁₀ and R₁₁, each independently represent ahydrogen atom, a halogen atom, a cyano group, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedC₃₋₈ cycloalkyl group, a group represented by the formula —CO—R₁₃, agroup represented by the formula —NR₁₄—CO—R₁₃, a group represented bythe formula —SO₂—R₁₅, a group represented by the formula —NR₁₄—SO₂—R₁₅,or a group represented by the formula —NR_(16a)R_(16b);

-   R₉ represents a group represented by the formula —NR_(16a)R_(16b) or    a group represented by the formula:

(wherein T2 represents an optionally substituted 5- to 10-memberedaromatic heterocycle or an optionally substituted 3- to 10-memberedheterocycle);R_(12a) and R_(12b) each independently represent a hydrogen atom, anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₃₋₆alkenyl group, an optionally substituted C₃₋₆ alkynyl group, anoptionally substituted C₃₋₈ cycloalkyl group, an optionally substituted3- to 10-membered heterocyclic group, or an optionally substituted C₁₋₆alkoxy group;

-   R₁₃ represents a hydrogen atom, an optionally substituted C₁₋₆ alkyl    group, an optionally substituted C₂₋₆ alkenyl group, an optionally    substituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈    cycloalkyl group, an optionally substituted C₆₋₁₀ aryl group, an    optionally substituted 5- to 10-membered heteroaryl group, an    optionally substituted 3- to 10-membered heterocyclic group, an    optionally substituted C₁₋₆ alkoxy group, an optionally substituted    C₆₋₁₀ aryloxy group, a group represented by the formula    —NR_(12a)R_(12b), or a group represented by the formula:

(wherein T2 represents an optionally substituted 5- to 10-memberedaromatic heterocycle or an optionally substituted 3- to 10-memberedheterocycle);

-   R₂ and R₁₄ each independently represent a hydrogen atom, an    optionally substituted C₁₋₆ alkyl group, an optionally substituted    C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynyl group, an    optionally substituted C₃₋₈ cycloalkyl group, or a group represented    by the formula —CO—R₁₃;-   R₁₅ represents an optionally substituted C₁₋₆ alkyl group, an    optionally substituted C₂₋₆ alkenyl group, an optionally substituted    C₂₋₆ alkynyl group, an optionally substituted C₃₋₈ cycloalkyl group,    an optionally substituted C₆-C₁₀ aryl group, an optionally    substituted 5- to 10-membered heteroaryl group, or an optionally    substituted 3- to 10-membered heterocyclic group;-   R_(16a) and R_(16b) each independently represent a hydrogen atom, an    optionally substituted C₁₋₆ alkyl group, an optionally substituted    C₃₋₆ alkenyl group, an optionally substituted C₃₋₆ alkynyl group, an    optionally substituted C₃₋₈ cycloalkyl group, an optionally    substituted C₆₋₁₀ aryl group, an optionally substituted 5- to    10-membered heteroaryl group, an optionally substituted 3- to    10-membered heterocyclic group, or an optionally substituted C₁₋₆    alkoxy group; and    X represents an oxygen atom, a sulfur atom, a carbonyl group, a    sulfonyl group, a group represented by the formula —CR_(X1)R_(X2)—,    or a group represented by the formula —NR_(X3)— (wherein R_(X1),    R_(X2) and R_(X3) each independently represent a hydrogen atom or a    group represented by the formula -A₁-A₂-A₃ (wherein A₁ and A₂ each    independently represent a single bond, an optionally substituted    C₁₋₆ alkylene group or a carbonyl group; and A₃ represents a    hydrogen atom, a C₃₋₈ cycloalkyl group, a group represented by the    formula —NR_(A1)R_(A2), or the formula —OR_(A3) (wherein, R_(A1),    R_(A2) and R_(A3) each independently represent a hydrogen atom or a    C₁₋₆ alkyl group), or an optionally substituted group represented by    the formula:

(wherein a represents 1 or 2))),a salt thereof, or a hydrate of the foregoing;<2> a compound represented by the general formula:

wherein X₁, X₂, Y, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ represent thesame definitions as X₁, X₂, Y, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ in<1>, respectively,a salt thereof, or a hydrate of the foregoing;<3> a compound according to <1> or <2>, a salt of the compound, or ahydrate of the foregoing, wherein Y represents an oxygen atom, a grouprepresented by the formula —NH—, or a group represented by the formula—N(CH₃)—;<4> a compound according to <1> or <2>, a salt of the compound, or ahydrate of the foregoing, wherein Y represents an oxygen atom;<5> a compound according to any of <1> to <4>, a salt of the compound,or a hydrate of the foregoing, wherein one of X₁ and X₂ represents agroup represented by the formula —CH═ and the other represents anitrogen atom;<6> a compound according to any of <1> to <4>, a salt of the compound,or a hydrate of the foregoing, wherein both X₁ and X₂ represent a grouprepresented by the formula —CH═;<7> a compound according to any of <1> to <6>, a salt of the compound,or a hydrate of the foregoing, wherein R₃, R₄, R₅, R₆ and R₈ eachrepresent a hydrogen atom, and R₇ represents a hydrogen atom, a halogenatom or an optionally substituted C₁₋₆ alkyl group;<8> a compound according to any of <1> to <7>, a salt of the compound,or a hydrate of the foregoing, wherein R₉ represents a group representedby the formula —NHR₁₇ (wherein R₁₇ represents an optionally substitutedC₁₋₆ alkyl group, a C₃₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, anoptionally substituted C₆₋₁₀ aryl group or an optionally substituted 5-to 10-membered heteroaryl group);<9> a compound according to any of <1> to <7>, a salt of the compound,or a hydrate of the foregoing, wherein R₉ represents a group representedby the formula —NR_(18a)R_(18b) (wherein R_(18a) and R_(18b) eachindependently represent a C₁₋₆ alkyl group);<10> a compound according to any of <1> to <7>, a salt of the compound,or a hydrate of the foregoing, wherein R₉ represents a group representedby the formula:

(wherein b₁ represents 1 or 2; X represents the same definition as X in<1>);<11> a compound according to any of <1> to <7>, a salt of the compound,or a hydrate of the foregoing, wherein R₉ represents a group representedby the formula —NHR₁₉ (wherein R₁₉ represents a C₁₋₆ alkyl group, a C₃₋₆alkynyl group, a C₃₋₈ cycloalkyl group or a C₆-C₁₀ aryl group);<12> a compound according to any of <1> to <11>, a salt of the compound,or a hydrate of the foregoing, wherein R₃, R₄, R₅, R₆, R₇ and R₈ eachrepresent a hydrogen atom;<13> a compound according to any of <1> to <12>, a salt of the compound,or a hydrate of the foregoing, wherein R₂ represents a hydrogen atom;<14> a compound according to any of <1> to <13>, a salt of the compound,or a hydrate of the foregoing, wherein R₉ represents a group representedby the formula —NHR₂₀ (wherein R₂₀ represents a methyl group, an ethylgroup or a cyclopropyl group);<15> a compound according to any of <1> to <13>, a salt of the compound,or a hydrate of the foregoing, wherein R₉ represents a group representedby the formula —NH(CH₃);<16> a compound according to any of <1> to <15>, a salt of the compound,or a hydrate of the foregoing, wherein R₁ represents a furtheroptionally substituted group represented by the formula:

(wherein b₂ represents 0, 1 or 2; and X represents the same definitionas X in <1>);<17> a compound according to any of <1> to <16>, a salt of the compound,or a hydrate of the foregoing, wherein R₁ represents a group representedby the formula:

(wherein X represents the same definition as X in <1>);<18> a compound according to <17>, a salt of the compound, or a hydrateof the foregoing, wherein X in the formula (IV) represents an oxygenatom;<19> a compound according to <17>, a salt of the compound, or a hydrateof the foregoing, wherein X in the formula (IV) represents a grouprepresented by the formula:

(wherein R_(X4) represents a hydrogen atom or a group represented by theformula -A₄-A₅-A₆ (wherein A₄ and A₅ each independently represent asingle bond, an optionally substituted C₁₋₆ alkylene or a carbonylgroup; and A₆ represents a hydrogen atom, a C₃₋₈ cycloalkyl group or agroup represented by the formula —NR_(A4)R_(A5) or the formula —OR_(A6)(wherein R_(A4), R_(A5) and R_(A6) each independently represent ahydrogen atom or a C₁₋₆ alkyl group)));<20> a compound according to <17>, a salt of the compound, or a hydrateof the foregoing, wherein X in the formula (IV) represents a grouprepresented by the formula:

(wherein R_(X5) and R_(X6) each independently represent a hydrogen atomor a group represented by the formula -A₇-A₈-A₉ (wherein A₇ and A₈ eachindependently represent a single bond, an optionally substituted C₁₋₆alkylene group or a carbonyl group; and A₉ represents a hydrogen atom, aC₃₋₈ cycloalkyl group, a group represented by the formula—NR_(A7)R_(A8), or the formula —OR_(A9) (wherein R_(A7), R_(A8), andR_(A9) each independently represent a hydrogen atom or a C₁₋₆ alkylgroup), or a group represented by the formula:

(wherein c₁ represents 0, 1 or 2)));<21> a compound according to <20>, a salt of the compound, or a hydrateof the foregoing, wherein one of R_(X5) and R_(X6) in the formula (VI)represents a hydroxyl group and the other represents a hydrogen atom ora C₁₋₆ alkyl group;<22> a compound according to <20>, a salt of the compound, or a hydrateof the foregoing, wherein one of R_(X5) or R_(X6) in the formula (VI)represents a hydrogen atom and the other represents a group representedby the formula:

(wherein c₂ represents 1 or 2);<23> a compound according to any of <1> to <16>, a salt of the compound,or a hydrate of the foregoing, wherein R₁ represents a group representedby the formula:

(wherein R_(X51) and R_(X61) each independently represent a hydrogenatom or a group represented by the formula -A₇₁-A₈₁-A₉₁ (wherein A₇₁ andA₈₁ each independently represent a single bond, an optionallysubstituted C₁₋₆ alkylene group or a carbonyl group; and A₉₁ representsa hydrogen atom, a C₃₋₈ cycloalkyl group, a group represented by theformula —NR_(A71)R_(A81), or the formula —OR_(A91) (wherein R_(A71),R_(A81), and R_(A91) each independently represent a hydrogen atom or aC₁₋₆ alkyl group), or a group represented by the formula:

(wherein c₁₁ represents 0, 1 or 2)));<24> A compound according to any of <1> to <15>, a salt of the compound,or a hydrate of the foregoing, wherein R₁ represents a group representedby the formula:

(wherein Y_(A1) and Y_(A2) each independently represent a grouprepresented by the formula -A₁₀-A₁₃-A₁₂ (wherein A₁₀ represents a singlebond or an optionally substituted C₁₋₆ alkylene group; A₁₁ represents asingle bond, an oxygen atom, a carbonyl group, or a sulfonyl group; andA₁₂ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ arylgroup, a 5- to 10-membered heteroaryl group, a group represented by theformula —NR_(A10)R_(A11), or the formula —OR_(A12) (wherein, R_(A10),R_(A11) and R_(A12) each independently represent a hydrogen atom, a C₁₋₆alkyl group or a C₃₋₈ cycloalkyl group), or a group represented by theformula:

(wherein e represents 1 or 2; and Z represents an oxygen atom or a grouprepresented by the formula —CR_(X7)R_(X8)— or the formula —NR_(X9)—(wherein R_(X7), R_(X8) and R_(X9) each independently represent ahydrogen atom, a hydroxyl group or a C₁₋₆ alkyl group))); and Y_(Z3)represents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup);<25> a compound according to <24>, a salt of the compound, or a hydrateof the foregoing, wherein one of Y_(A1) and Y_(A2) in the formula (VIII)represents a hydrogen atom and the other represents a group representedby the formula —(CH₂)₂-A₁₃-A₁₄ (wherein A₁₃ represents a single bond, acarbonyl group or a sulfonyl group; and A₁₄ represents a C₁₋₆ alkylgroup, a group represented by the formula —NR_(A13)R_(A14) (whereinR_(A13) and R_(A14) each independently represent a hydrogen atom, a C₁₋₆alkyl group or a C₃₋₈ cycloalkyl group), or a group represented by theformula:

(wherein e and Z represent the same definitions as e and Z in <24>,respectively)))); and Y_(A3) in the formula (VIII) represents a hydrogenatom;<26> a compound according to any of <1> to <15>, a salt of the compound,or a hydrate of the foregoing, wherein R₁ represents a group representedby the formulas:

(each of the foregoing members being optionally substituted with a groupselected from Substituent Group Alpha,wherein Substituent Group Alpha is a group consisting of a halogen atom,a hydroxyl group, a thiol group, a nitro group, a cyano group, acarboxyl group, an amino group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkylgroup, and a group represented by the formulas:

(wherein R_(N1) and R_(N2) each independently represent a hydrogen atomor a C₁₋₆ alkyl group));<27> a compound according to any of <1> to <15>, a salt of the compound,or a hydrate of the foregoing, wherein R₁ represents a group representedby the formulas:

<28> a compound according to any of <1> to <15>, a salt of the compound,or a hydrate of the foregoing, wherein R₁ represents a group representedby the formulas:

<29> a compound according to any of <1> to <15>, a salt of the compound,or a hydrate of the foregoing, wherein R₁ represents a group representedby the formulas:

<30> a compound according to <1> or <2>, a salt of the compound, or ahydrate of the foregoing, wherein the compound is represented by thegeneral formula:

(wherein R₁ represents a group represented by the formulas:

(each of the foregoing members being optionally substituted with a groupselected from Substituent Group Beta,wherein Substituent Group Beta is a group consisting of a hydroxylgroup, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, and a grouprepresented by the formulas:

(wherein R_(N1) and R_(N2) each independently represent a hydrogen atomor a C₁₋₆ alkyl group)); and R₉ represents a group represented by theformula —NHR₂₀ (wherein R₂₀ represents a methyl group, an ethyl group ora cyclopropyl group));<31> a compound according to <1>, a salt of the compound, or a hydrateof the foregoing, wherein the compound is a compound selected from agroup consisting of

-   (1)    N1-ethyl-5-(2-((methoxylamino)carbonyl)amino-4-pyrimidyl)oxy-1H-indolecarboxamide,-   (2)    5-(6-(3-(3-diethylaminopropylamino)ureido)pyrimidin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (3)    5-(6-(((4-hydroxypiperidin-1-yl)carbonyl)amino)-pyrimidin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (4)    5-(6-((4-pyrrolidin-1-yl)piperidin-1-yl)carbonylamino)pyrimidin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (5)    5-(2-(3-((1R)-1-carbamoyl-2-phenylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (6)    5-(2-(3-((1S)-1-carbamoyl-2-phenylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (7)    5-(2-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (8)    5-(2-(3-(2-(4-hydroxy-4-methylpiperidin-1-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (9)    5-(2-(3-((1S)-1-carbamoylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (10)    5-(2-(3-((1S)-1-carbamoyl-3-methylbutyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (11)    5-(2-(3-carbamoylmethylureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (12)    5-(2-(3-cyclopropylcarbamoylmethylureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (13)    5-(2-(3-((1S)-1-carbamoyl-2-hydroxyethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (14)    5-(2-(3-((1R)-1-carbamoyl-2-hydroxyethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (15)    (2S)-2-(3-(4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)ureido)-1,5-pentanedicarboxylic    acid diamide,-   (16)    (2S)-2-(3-(4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)ureido)succinamide,-   (17)    5-(2-(3-((1S)-1-cyclopropylcarbamoyl-2-hydroxyethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (18)    5-(2-(3-((1S)-1-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (19)    5-(2-(3-((1R)-1-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (20)    5-(2-(3-((1S)-1-hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (21)    5-(2-(3-((1R)-1-hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (22)    5-(2-(3-((1S)-1-hydroxymethyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (23)    5-(2-(3-((1S)-1-hydroxymethyl-2-(morpholin-4-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (24)    5-(2-(3-(2-cyclopropylcarbamoylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (25)    5-(2-(3-(3-oxo-3-(pyrrolidin-1-yl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (26)    5-(2-(3-(3-(4-hydroxy-4-methylpiperidin-1-yl)-3-oxopropyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (27)    N1-ethyl-5-(2-(((2-ethoxyethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (28)    N1-methyl-5-(2-((4-(2-hydroxy-2-methylpropionyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (29)    N1-methyl-5-(2-((3-(diethylamino)propylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (30)    N1-methyl-5-(2-(((3-(4-hydroxypiperidino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (31)    N1-methyl-5-(2-(((3-(4-methylpiperazin-1-yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (32)    5-(2-(3-(4-oxo-4-(pyrrolidin-1-yl)butyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (33)    5-(2-(3-(3-(cyclopropylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (34)    5-(2-(3-(4-(4-hydroxy-4-methylpiperidin-1-yl)-4-oxobutyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (35)    5-(2-(3-(3-(diethylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (36)    5-(2-(3-(3-(methylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (37)    N1-methyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (38)    N1-methyl-5-(2-(piperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (39)    N1-methyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (40)    N1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (41)    5-(2-(((4-hydroxy-4-methylpiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (42)    N1-methyl-5-(2-((4-(1-hydroxy-1-methylethyl)piperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (43)    5-(2-(((4-(3-methylcarbamoylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (44)    5-(2-(((4-(3-carbamoylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (45)    5-(2-((4-((pyrrolidin-1-yl)carbonyl)piperidin-1-yl)carbonylamino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (46)    N1-methyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (47)    N1-methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (48)    N1-methyl-5-(2-((4-ethylpiperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (49)    N1-methyl-5-(2-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (50)    N1-methyl-5-(2-((3-methylsulfonylpropylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (51)    N1-methyl-5-(2-((4-(2-dimethylaminoacetyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (52)    N1-methyl-5-(2-((4-cyclohexylpiperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (53)    N4-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,-   (54)    N1-methyl-5-(2-((1,1-dioxothiomorpholin-4-ylcarbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (55)    5-(2-(3-((1R)-1-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid ethylamide,-   (56)    5-(2-(3-((1S)-1-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid ethylamide,-   (57)    5-(2-(3-((1R)-1-hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid ethylamide,-   (58)    5-(2-(3-((1S)-1-hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid ethylamide,-   (59)    5-(2-(3-(2-(4-hydroxy-4-methylpiperidin-1-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid ethylamide,-   (60)    N1-ethyl-5-(2-((((1-methyl-4-piperidyl)methyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (61)    N1-ethyl-5-(2-(((2-diethylamino)ethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (62)    N1-ethyl-5-(2-(((2-(morpholin-4-yl)ethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (63)    N1-ethyl-5-(2-(((2-(4-hydroxypiperidino)ethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (64)    N1-methyl-5-(2-(((2-(4-hydroxypiperidino)ethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (65)    N1-ethyl-5-(2-((3-(diethylamino)propylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (66)    N1-ethyl-5-(2-(((3-(morpholin-4-yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (67)    N1-ethyl-5-(2-(((3-(4-methylpiperazin-1-yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (68)    N1-cyclopropyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (69)    5-(2-(3-((1R)-1-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid cyclopropylamide,-   (70)    5-(2-(3-((1S)-1-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid cyclopropylamide,-   (71)    5-(2-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid cyclopropylamide,-   (72)    5-(2-(3-(3-oxo-3-(pyrrolidin-1-yl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid cyclopropylamide,-   (73)    5-(2-(3-((1R)-1-hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid cyclopropylamide,-   (74)    5-(2-(3-((1S)-1-hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid cyclopropylamide,-   (75)    N1-phenyl-5-(2-(((3-(diethylamino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (76)    N1-phenyl-5-(2-(((3-(4-methylpiperazin-1-yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (77)    N1-ethyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (78)    5-(2-(((4-hydroxy-4-methylpiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid ethylamide,-   (79)    N1-ethyl-5-(2-((4-hydroxypiperidin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (80)    N1-ethyl-5-(2-(piperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (81)    N1-ethyl-5-((2-((pyrrolidin-1-ylcarbonyl)amino)-4-pyridyl)oxy)-1H-1-indolecarboxamide,-   (82)    N4-(4-((1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-4-morpholinecarboxamide,-   (83)    N1-ethyl-5-(2-((1,1-dioxothiomorpholin-4-ylcarbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (84)    N1-ethyl-5-(2-((methoxylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (85)    N1-cyclopropyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (86)    N1-cyclopropyl-5-(2-(((4-hydroxy-4-methylpiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarbox-amide,-   (87)    N4-(4-(1-(cyclopropylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,-   (88)    N1-cyclopropyl-5-(2-((pyrrolidin-1-ylcarbonyl)amino)-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (89)    N1-cyclopropyl-5-(2-(piperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (90)    N4-(4-(1-(cyclopentylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,-   (91)    5-(2-(((4-hydroxypiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid cyclopentylamide,-   (92)    N1-cyclopentyl-5-(2-((4-(pyrrolidin-1-yl)piperidin-1-ylcarbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (93)    N1-(3-methylbutyl)-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (94)    N1-(3-methylbutyl)-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (95)    N4-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,-   (96)    N1-(1-ethylpropyl)-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (97)    N1-(1-ethylpropyl)-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (98)    N4-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,-   (99)    N4-(4-(1-((1-pentyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,-   (100)    N1-(1-pentyl)-5-(2-(((4-hydroxypiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (101)    N1-(1-pentyl)-5-(2-((4-(pyrrolidin-1-yl)piperidin-1-ylcarbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (102)    N1-methyl-3-chloro-5-(2-(((3-(diethylamino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (103)    N1-methyl-3-chloro-5-(2-((4-(pyrrolidin-1-yl)piperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (104)    N1-methyl-3-chloro-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (105)    N1-methyl-3-chloro-5-(2-(((3-(4-hydroxypiperidino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (106)    N1-methyl-3-chloro-5-(2-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (107)    N4-(4-(3-chloro-1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,-   (108)    N1-methyl-3-chloro-5-(2-((4-(ethylpiperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (109)    N1-ethyl-3-chloro-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (110)    N1-ethyl-3-chloro-5-(2-(((3-(4-hydroxypiperidino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (111)    N1-ethyl-3-chloro-5-(2-(((3-(diethylamino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (112)    N1,3-dimethyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (113)    N1,3-dimethyl-5-(2-((4-(pyrrolidin-1-yl)piperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (114)    N1-cylopropyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-3-methyl-1H-1-indolecarboxamide,-   (115)    N1-cylopropyl-5-(2-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-3-methyl-1H-1-indolecarboxamide,-   (116)    N1-methyl-5-(2-((methylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (117)    N1-methyl-5-(2-((diethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (118)    N1-(2-propynyl)-5-(2-((pyrrolidin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;-   (119)    N1-methyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (120)    N1-ethyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (121)    N1-cyclopropyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (122)    N1-methyl-5-(2-(((4-(morpholin-4-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (123)    N1-methyl-5-(2-(((4-(azetidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,

(124)N1-methyl-5-(2-(((4-(diethylamino)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,

-   (125)    N1-methyl-5-(2-(((4-(4-hydroxypiperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,    and-   (126)    N1-propyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;    <32> a compound according to <1>, a salt of the compound, or a    hydrate of the foregoing, wherein the compound is a compound    selected from a group consisting of-   (1)    5-(2-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (2)    5-(2-(3-carbamoylmethylureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (3)    5-(2-(3-((1S)-1-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (4)    N1-methyl-5-(2-((4-(2-hydroxy-2-methylpropionyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (5)    5-(2-(3-(4-oxo-4-(pyrrolidin-1-yl)butyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (6)    5-(2-(3-(3-(cyclopropylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (7)    5-(2-(3-(4-(4-hydroxy-4-methylpiperidin-1-yl)-4-oxobutyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (8)    5-(2-(3-(3-(methylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (9)    N1-methyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (10)    N1-methyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (11)    N1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (12)    5-(2-(((4-hydroxy-4-methylpiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (13)    5-(2-(((4-(3-methylcarbamoylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (14)    5-(2-(((4-(3-carbamoylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (15)    N1-methyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (16)    N1-methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (17)    N1-methyl-5-(2-((3-methylsulfonylpropylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (18)    N4-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,-   (19)    N1-cyclopropyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (20)    5-(2-(((4-hydroxy-4-methylpiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid ethylamide,-   (21)    N1-ethyl-5-(2-((4-hydroxypiperidin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (22)    N1-ethyl-5-((2-((pyrrolidin-1-ylcarbonyl)amino)-4-pyridyl)oxy)-1H-1-indolecarboxamide,-   (23)    N4-(4-((1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-4-morpholinecarboxamide,-   (24)    N1-cyclopropyl-5-(2-((pyrrolidin-1-ylcarbonyl)amino)-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (25)    N1-methyl-3-chloro-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (26)    N1-methyl-5-(2-((methylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (27)    N1-methyl-5-(2-((diethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (28)    N1-(2-propynyl)-5-(2-((pyrrolidin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (29)    N1-methyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (30)    N1-ethyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (31)    N1-cyclopropyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (32)    N1-methyl-5-(2-(((4-(morpholin-4-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (33)    N1-methyl-5-(2-(((4-(azetidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (34)    N1-methyl-5-(2-(((4-(diethylamino)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (35)    N1-methyl-5-(2-(((4-(4-hydroxypiperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,    and-   (36)    N1-propyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;    <33> a compound according to <1>, a salt of the compound, or a    hydrate of the foregoing, wherein the compound is a compound    selected from a group consisting of-   (1)    5-(2-(((4-hydroxy-4-methylpiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylic    acid methylamide,-   (2)    N1-methyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide,-   (3)    N1-methyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,-   (4)    N1-methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide,    and-   (5)    N4-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide;    <34> a pharmaceutical composition comprising a compound according to    any of <1> to <33> and a pharmaceutical adjuvant;    <35> a prophylactic or therapeutic agent for a disease for which    angiogenesis inhibition is effective, comprising as an active    ingredient, a compound according to any of <1> to <33>, a salt    thereof, or a hydrate of the foregoing;    <36> an angiogenesis inhibitor comprising as an active ingredient, a    compound according to any of <1> to <33>, a salt thereof, or a    hydrate of the foregoing;    <37> an antitumor agent comprising as an active ingredient, a    compound according to any of <1> to <33>, a salt thereof, or a    hydrate of the foregoing;    <38> an antitumor agent according to <37>, wherein the tumor is a    pancreatic cancer, a gastric cancer, a colon cancer, a breast    cancer, a prostate cancer, a lung cancer, a renal cancer, a brain    tumor, a blood cancer, or an ovarian cancer;    <39> a therapeutic agent for hemangioma comprising as an active    ingredient, a compound according to any of <1> to <33>, a salt    thereof, or a hydrate of the foregoing;    <40> a cancer metastasis inhibitor comprising as an active    ingredient, a compound according to any of <1> to <33>, a salt    thereof, or a hydrate of the foregoing;    <41> a therapeutic agent for retinal neovascularization or diabetic    retinopathy comprising as an active ingredient, a compound according    to any of <1> to <33>, a salt thereof, or a hydrate of the    foregoing;    <42> a therapeutic agent for an inflammatory disease comprising as    an active ingredient, a compound according to any of <1> to <33>, a    salt thereof, or a hydrate of the foregoing;    <43> a therapeutic agent for an inflammatory disease according to    <42>, wherein the inflammatory disease is deformant arthritis,    rheumatoid arthritis, psoriasis or delayed hypersensitivity    reaction;    <44> a therapeutic agent for atherosclerosis comprising as an active    ingredient, a compound according to any of <1> to <33>, a salt    thereof, or a hydrate of the foregoing;    <45> an angiogenesis inhibition-based antitumor agent comprising as    an active ingredient, a compound according to any of <1> to <33>, a    salt thereof, or a hydrate of the foregoing;    <46> a prophylactic or therapeutic method for a disease for which    angiogenesis inhibition is effective, comprising administering to a    patient, a pharmacologically effective dose of a compound according    to any of <1> to <33>, a salt thereof, or a hydrate of the    foregoing; and    <47> use of a compound according to any of <1> to <33>, a salt    thereof, or a hydrate of the foregoing for the manufacture of a    prophylactic or therapeutic agent for a disease for which    angiogenesis inhibition is effective.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The meanings of the terms, symbols or the like used in the specificationare described and the present invention is described in detail below.

It should be noted that, although the structural formula of a compoundmay indicate a certain isomer for convenience's sake in thisspecification, the present invention include all geometrical isomersgenerated in the structures of compounds, isomers such as opticalisomers based on asymmetric carbon atom, stereoisomers and tautomers,and a mixture of isomers, which are not limited to the descriptions offormulas for convenience's sake, either of isomers or mixtures may beincluded. Therefore, although optically active compounds and racemiccompounds may be existent when they have asymmetric carbon atoms in amolecule, they are not particularly limited in the present invention andany cases are included. In addition, although a variety of crystalmorphism are existent, these are not limited similarly. Specifically,any of a single crystal form or mixtures may be included, in addition,anhydrates, hydrates or solvates may be included.

In addition, compounds according to the present invention also includecompounds which still indicate a desired activity after they aresubjected to metabolism such as oxidation, reduction, hydrolysis andconjugation in an organism, and the present invention also includescompounds which produce the compounds according to the present inventionafter they are subjected to metabolism such as oxidation, reduction andhydrolysis.

The term “C₁₋₆ alkyl group” as described in the specification representsa linear or branched alkyl group of 1 to 6 carbon atoms, which is amonovalent group derived by removing a hydrogen atom from an aliphatichydrocarbon of 1 to 6 carbon atoms. As specific examples there may bementioned methyl group, ethyl group, n-propyl group, i-propyl group,n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n-pentylgroup, i-pentyl group, sec-pentyl group, neopentyl group, 1-methylbutylgroup, 2-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropylgroup, n-hexyl group, i-hexyl group, 1-methylpentyl group,2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group,1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutylgroup, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutylgroup, 2-ethylbutyl group, 1,1,2-trimethylpropyl group,1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group,1-ethyl-2-methylpropyl group or the like, and preferably methyl group,ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butylgroup, sec-butyl group and t-butyl group.

The term “C₂₋₆ alkenyl group” as described in the specificationrepresents a linear or branched alkenyl group of 2 to 6 carbon atomswhich may contain 1 to 2 double bonds. As specific examples there may bementioned ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenylgroup, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group,pentenyl group, hexenyl group, hexandienyl group or the like, andpreferably ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenylgroup, 2-butenyl group, 3-butenyl group and 2-methyl-1-propenyl group.

The term “C₃₋₆ alkenyl group” as described in the specificationrepresents a linear or branched alkenyl of 3 to 6 carbon atoms which maycontain 1 to 2 double bonds. As specific examples there may be mentioned1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group,3-butenyl group, 2-methyl-1-propenyl group, pentenyl group, hexenylgroup, hexandienyl group or the like, and preferably 1-propenyl group,2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group and2-methyl-1-propenyl group.

The term “C₂₋₆ alkynyl group” as described in the specificationrepresents a linear or branched alkynyl group of 2 to 6 carbon atomswhich may contain 1 to 2 triple bonds. As specific examples there may bementioned ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynylgroup, 2-butynyl group, 3-butynyl group, pentynyl group, hexynyl group,hexandiynyl group or the like, and preferably ethynyl group, 1-propynylgroup, 2-propynyl group, 1-butynyl group, 2-butynyl group and 3-butynylgroup.

The term “C₃₋₆ alkynyl group” as described in the specificationrepresents a linear or branched alkynyl group of 3 to 6 carbon atomswhich may contain 1 to 2 triple bonds. As specific examples there may bementioned 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynylgroup, 3-butynyl group, pentynyl group, hexynyl group, hexandiynyl groupor the like, and preferably 1-propynyl group, 2-propynyl group,1-butynyl group, 2-butynyl group and 3-butynyl group.

The term “C₃₋₈ cycloalkyl group” as described in the specificationrepresents a cyclic aliphatic hydrocarbon group of 3 to 8 carbon atoms,and as specific examples there may be mentioned cyclopropyl group,cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptylgroup, cyclooctyl group or the like, and preferably cyclopropyl group,cyclobutyl group and cyclopentyl group.

The term “C₁₋₆ alkylene group” as described in the specificationrepresents a divalent group derived by further removing a hydrogen atomfrom the aforementioned definition of “C₁₋₆ alkyl group.” As specificexamples there may be mentioned methylene group, ethylene group,methylethylene group, propylene group, ethylethylene group,1,1-dimethylethylene group, 1,2-dimethylethylene group, tetramethylenegroup, pentamethylene group, hexamethylene group or the like, andpreferably methylene group and ethylene group.

The term “C₁₋₆ alkoxy group” as described in the specificationrepresents an oxy group bonded with the aforementioned definition of“C₁₋₆ alkyl group.” As specific examples there may be mentioned methoxygroup, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group,i-butoxy group, sec-butoxy group, t-butoxy group, n-pentyloxy group,i-pentyloxy group, sec-pentyloxy group, neopentyloxy group,1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylpropoxy group,1,2-dimethylpropoxy group, n-hexyloxy group, i-hexyloxy group,1-methylpentyloxy group, 2-menthylpentyloxy group, 3-methylpentyloxygroup, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group,2,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxygroup, 3,3-dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxygroup, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group,1-ethyl-1-methylpropoxy group, 1-ethyl-2-methylpropoxy group or thelike, and preferably methoxy group, ethoxy group, n-propoxy group,i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, andt-butoxy group.

The term “C₁₋₆ alkylthio group” as described in the specificationrepresents a thio group bonded with the aforementioned definition of“C₁₋₆ alkyl group.” As specific examples there may be mentionedmethylthio group, ethylthio group, n-propylthio group, i-propylthiogroup, n-butylthio group, i-butylthio group, sec-butylthio group,t-butylthio group, n-pentylthio group, i-pentylthio group,sec-pentylthio group, neopentylthio group, 1-methylbutylthio group,2-methylbutylthio group, 1,1-dimethylpropylthio group,1,2-dimethylpropylthio group, n-hexylthio group, i-hexylthio group,1-methylpentylthio group, 2-methylpentylthio group, 3-methylpentylthiogroup, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group,2,2-dimethylbutylthio group, 1,3-dimethylbutylthio group,2,3-dimethylbutylthio group, 3,3-dimethylbutylthio group,1-ethylbutylthio group, 2-ethylbutylthio group,1,1,2-trimethylpropylthio group, 1,2,2-trimethylpropylthio group,1-ethyl-1-methylpropylthio group, 1-ethyl-2-methylpropylthio group orthe like, and preferably methylthio group, ethylthio group, n-propylthiogroup, i-propylthio group, n-butylthio group, i-butylthio group,sec-butylthio group and t-butylthio group.

The term “C₆₋₁₀ aryl group” as described in the specification representsan aromatic hydrocarbon ring group of 6 to 10 carbon atoms. As specificexamples there may be mentioned phenyl group, 1-naphthyl group,2-naphthyl group, indenyl group, azulenyl group, heptalenyl group or thelike, and preferably phenyl group, 1-naphthyl group and 2-naphthylgroup.

The term “C₆₋₁₀ aryloxy group” as described in the specificationrepresents an oxy group bonded with the aforementioned definition of“C₆₋₁₀ aryl group.” As specific examples there may be mentioned phenoxygroup, 1-naphthyloxy group, 2-naphthyloxy group, indenyloxy group,azulenyloxy group, heptalenyloxy group or the like, and preferablyphenoxy group, 1-naphthyloxy group and 2-naphthyloxy group.

The term “halogen atom” as described in the specification representsfluorine atom, chlorine atom, bromine atom or iodine atom, andpreferably fluorine atom, chlorine atom and bromine atom.

The term “heteroatom” as described in the specification representsnitrogen atom, sulfur atom, or oxygen atom.

The term “5- to 10-membered aromatic heterocycle” as described in thespecification represents an aromatic ring in which the number of atomsforming the ring is 5 to 10, and 1 to a plurality of heteroatoms arecontained in the atoms forming the ring. Specific examples are pyrrolering, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring,pyrazole ring, imidazole ring, triazole ring, tetrazole ring, indolering, isoindole ring, indazole ring, quinoline ring, isoquinoline ring,cinnoline ring, quinazoline ring, quinoxaline ring, naphthyridine ring,phthalazine ring, carbazole ring, purine ring, furan ring, thiophenering, benzimidazole ring, imidazopyridine ring, imidazotriazine ring,pyrrolopyridine ring, pyrrolopyrimidine ring, pyridopyrimidine ring,oxazole ring, isoxazole ring, thiazole ring, isothiazole ring,phenoxazine ring, phenothiazine ring, furopyrrole ring, imidazothiazolering, benzoxazole ring, benzthiazole ring, pyrazoloxazole ring,pyridoxazine ring, benzofuran ring, benzothiophene ring or the like, andpreferably furan ring, thiophen ring, and thiazole ring.

The term “5- to 10-membered heteroaryl group” as described in thespecification represents a monovalent group derived by removing ahydrogen atom from the aforementioned definition of “5- to 10-memberedaromatic heterocycle.”

The term “3- to 10-membered heterocycle” as described in thespecification represents,

-   (1) a monocyclic or bicyclic non-aromatic ring-   (2) having 3 to 10 atoms in the ring,-   (3) containing 1 to 2 hetero atoms among the atoms of the ring,-   (4) optionally including 1 to 2 double bonds in the ring, and-   (5) optionally including 1 to 3 carbonyl groups or 1 to 3 sulfonyl    groups in the ring.    Specific examples are aziridine ring, azetidine ring, pyrrolidine    ring, piperidine ring, 4-oxopiperidine ring, homopiperidine ring,    piperazine ring, homopiperazine ring, morpholine ring,    thiomorpholine ring, 1,1-dioxothiomorpholine ring, pyridone ring,    phthalimide ring, succinimide ring or the like, and preferably    azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring,    morpholine ring and thiomorpholine ring.

The term “3- to 10-membered heterocyclic group” as described in thespecification represents a monovalent group derived by removing ahydrogen atom from the aforementioned definition of “3- to 10-memberedheterocycle.”

The term “optionally substituted” as described in the specification isequivalent in the meaning as in “which may have 1 or a plurality ofsubstituents by arbitrarily combining them at substitutable positions”.As specific examples of such substituents there may be mentioned thefollowing:

-   (1) a halogen atom,-   (2) a hydroxyl group,-   (3) a thiol group,-   (4) a nitro group,-   (5) a cyano group,-   (6) an azido group,-   (7) a formyl group,-   (8) a carboxyl group,-   (9) an amino group,-   (10) an oxo group or-   (11) a group represented by the formula -T¹-T²-T³, wherein T¹    represents a single bond or a C₁₋₆ alkylene group; T² represents a    single bond, a C₁₋₆ alkylene group, an oxygen atom, an sulfur atom,    a sulfinyl group, a sulfonyl group, a carbonyl group, or a group    represented by the formula —O—CO—, the formula —CO—O—, the formula    —NR^(T1)—, the formula —CO—NR^(T1)—, the formula —NR^(T1)—CO—, the    formula —SO₂—NR^(T1)—, or the formula —NR^(T1)—SO₂—; T³ represents a    hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆    alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a 5- to    10-membered heteroaryl group, a 3- to 10-membered heterocyclic group    or a group represented by the formula —N(R^(T2)) (R^(T3)) R^(T1),    R^(T2), or R^(T3) each independently represent a hydrogen atom or a    C₁₋₆ alkyl group; wherein a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,    a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a    5- to 10-membered heteroaryl group and a 3- to 10-membered    heterocyclic group in T³ may each independently have 1 to 3 groups    selected from a group of the below-mentioned Substituent Group;    <Substituent Group>    a halogen atom, a hydroxyl group, a thiol group, a nitro group, a    cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, a C₂₋₆    alkenyl group, a C₂₋₆ alkynyl group, a C₆₋₁₀ aryl group, a 5- to    10-membered heteroaryl group, a 3- to 10-membered heterocyclic    group, a C₁₋₆ alkoxy group and a C₁₋₆ alkylthio group.

The term “leaving group” as described in the specification may be anygroup commonly known as a leaving group in organic synthesis, with nospecial restrictions, and as specific examples there may be mentioned ahalogen atom such as a chlorine atom, a bromine atom, an iodine atom; anitro group; an alkylthio group such as a methylthio group, an ethylthiogroup and a propylthio group; an arylthio group such as a phenylthiogroup, a toluylthio group and a 2-pyridylthio group; an alkylsulfonyloxygroup such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxygroup, an ethanesulfonyloxy group, a propanesulfonyloxy; anarylsulfonyloxy group such as a benzenesulfonyloxy group, ap-toluenesulfonyloxy group; an alkanoyloxy group such as an acetoxygroup and a trifluoroacetoxy group; an alkoxy group such as a methoxygroup, an ethoxy group and a propoxy group; an alkylamino group such asa methylamino group, an ethylamino group, a propylamino group and abutylamino group; a dialkylamino group such as a dimethylamino group, adiethylamino group, a dipropylamino group, a methylethylamino group, anethylpropylamino group and a methylpropylamino group; a substitutedphosphoryloxy group such as diphenoxyphosphoryloxy group or the like,and preferably a halogen atom such as a chlorine atom, a bromine atomand an iodine atom, a trifluoromethanesulfonyl group or the like.

As a “salt” described in the specification, there may be mentioned, forexample, a salt with inorganic acid, a salt with organic acid, a saltwith inorganic base, a salt with organic base, a salt with acidic orbasic amino acid or the like, preferably a pharmacologically acceptablesalt. A salt is formed in an appropriate ratio of 0.1 to 5 molecules ofacid or base to one molecule of the compound.

As preferable examples of a salt with inorganic acid, there may bementioned, for example, a salt with hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, or the like, and aspreferable examples of a salt with organic acid, there may be mentioned,for example, a salt with acetic acid, succinic acid, fumaric acid,maleic acid, tartaric acid, citric acid, lactic acid, stearic acid,benzoic acid, methanesulfonic acid, p-toluenesulfonic acid or the like.

As preferable examples of a salt with inorganic base, there may bementioned, for example, an alkali metal salt such as a sodium salt and apotassium salt, an alkali earth metal salt such as a calcium salt and amagnesium salt, an aluminum salt, an ammonium salt or the like. Aspreferable examples of a salt with organic base, there may be mentioned,for example, a salt with diethylamine, diethanolamine, meglumine,N,N′-dibenzylethylenediamine or the like.

As preferable examples of a salt with acidic amino acid, there may bementioned, for example, a salt with aspartic acid, glutamic acid or thelike, and as preferable examples of a salt with basic amino acid, theremay be mentioned, for example, a salt with arginine, lysine, ornithineor the like.

As a “adjuvant” described in the specification, there may be mentioned,for example, a excipient, a binder, a disintegrator, a lubricant, acoloring agent, a corrective coating, a stabilizer, a emulsifier, aabsorbefacient, a surfactant, a pH adjustor, a preservative, anantioxidant or the like.

Production methods for the compounds of the invention will now bedescribed. Various methods may be considered for production of compoundsof the invention represented by the general formulas (I) and (II) withsynthesis carried out by ordinary organic synthesis means, and thefollowing are representative examples of methods for their production.

[General Synthesis Method]

[Production Method 1]

A typical production method of the compound represented by the formula(Ia)

wherein, R₁₀₁, R₁₀₂ may represent the same definitions as the formulaR_(12a), R_(12b) (R_(12a) and R_(12b) represent the same definitions asthe aforementioned definition), respectively; or R₁₀₁ and R₁₀₂ form aring, and the formula —NR₁₀₁R₁₀₂ may represent the same definition asthe formula

(wherein T1 represents the same definition as the aforementioneddefinition); other symbols represent the same definitions as theaforementioned definitions.

[Production Method 1-A]

A typical production method of the compound (1e), which is the compoundsrepresented by the formula (Ia), wherein Y represents an oxygen atom, asulfur atom or a group represented by the formula —NR_(Y)— (R_(Y)represents a hydrogen atom or a C₁₋₆ alkyl group)

wherein, Y₁ represents an oxygen atom, a sulfur atom or a grouprepresented by the formula —NR_(Y1)— (R_(Y1) represents a hydrogen atomor a C₁₋₆ alkyl group); L₁ represents a leaving group; other symbolsrepresent the same definitions as the aforementioned definition.<Step 1A-1>

This is a step for obtaining a compound (1c) by condensing pyrimidine ora pyridine derivative (1a) having a leaving group (L₁) at the 4-positionwith an indole derivative (1b). As a reaction solvent,N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide,2-ethoxyethanol, chlorobenzene or the like can be used. A base or anacid may be added thereto, specifically, an organic base such asdiisopropylethylamine, an inorganic base such as potassium carbonate,cesium carbonate and sodium hydride and an acid such as pyridinehydrochloride and hydrochloric acid can be used. The reaction can beperformed at a temperature ranging from room temperature to refluxtemperature for a reaction time ranging from 10 minutes to 30 hours. Inaddition, a compound where a halogen atom which is not as a leavinggroup is bonded on pyrimidine or pyridine ring may be used as a startingmaterial, and the halogen atom can be reduced by the catalytic reductionmethod or the like after this step.

<Step 1A-2>

This is a step for obtaining a compound (1d) by carboxamidating the1-position of indole in compound (1c). As a reagent, a carbamatederivative, an isocyanate derivative, a halogenated carbamoyl derivativeor the like can be used. As a reaction solvent, chloroform, toluene,N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide,chlorobenzene can be used. A base may be added thereto, specifically, anorganic base such as pyridine, triethylamine and diisopropylethylamine,an inorganic base such as potassium carbonate, cesium carbonate andsodium hydride can be used, for example. The reaction can be performedfor a time of 10 minutes to 30 hours at a temperature of 0° C. to refluxtemperature.

<Step 1A-3>

This is a step for converting a compound (1d) into a urea derivative(1e). Carbamate ester derivative is prepared by using phenylchlorocarbonate or the like as a reagent, for example. After thisintermediate is isolated, or not isolated, the intermediate is allowedto react with an amine, thereby a urea derivative can be obtained.Alternatively, by reacting a carbamate derivative or an isocyanatederivative as a reagent, a corresponding urea derivative can beconverted into. As a reaction solvent, chloroform, toluene,N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide,chlorobenzene or the like can be used. A base may be added thereto,specifically, an organic base such as pyridine, triethylamine, anddiisopropylethylamine, an inorganic base such as potassium carbonate,cesium carbonate and sodium hydride can be used, for example. Thereaction can be performed for a time of 10 minutes to 30 hours at atemperature of 0° C. to reflux temperature.

It should be noted that a substituent conversion in R₂, R₁₀₁, R₁₀₂ canbe also performed by suitably using an oxidation reaction, a reductionreaction, a reductive amination reaction, an ester formation reaction,an amide formation reaction, a protecting group introduction reaction, adeprotection reaction, a hydrolysis reaction or the like which aregenerally used before and/or after each process. Specifically, forexample, in the case that R₂ is a hydrogen atom in the compounds (1a),(1c) and (1d), the following methods come under the above-mentionedsubstituent conversions; that is, a method for converting R₂ into a C₁₋₆alkyl group by performing a reductive amination reaction with aldehydeor ketone, a method in which, after a corresponding urea derivative isobtained as in <Step 1A-3> from the compound (1c) and an amine havingketone or aldehyde, an amine side chain is introduced into R₁₀₁, R₁₀₂ byfurther performing a reductive amination reaction with an amine, or thelike. In these cases, sodium cyanoborohydride, sodiumtrimethoxyborohydride, sodium triacetoxyborohydride or the like can beused as a reducing agent, and methanol, tetrahydrofuran,dichloromethane, dichloroethane or the like can be used as a reactionsolvent. In addition, a method that a benzotriazole derivative isprepared and the derivative is reduced by sodium borohydride as reportedin Tetrahedron 47, 2683 (1991), or the like is useful. Alternatively, acorresponding urea is formed as in <Step 1A-3> from the compound (1c)and an amine having an ester. After the ester is hydrolyzed by basessuch as lithium hydroxide, sodium hydroxide or potassium hydroxide inaqueous ethanol, an amide derivative can be also obtained by using acondensing agent. In this case, N,N-dimethylformamide, tetrahydrofuranor the like can be used as a reaction solvent, and1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride,(1H-1,2,3-benzotriazole-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate can be used as a condensing agent. The reaction canbe performed for a time of 10 minutes to 30 hours at a temperature of 0°C. to reflux temperature.

[Production Method 1-B]

A production method of the compound (1g), which is the compoundrepresented by the formula (Ia), wherein Y is a sulfinyl group or asulfonyl group

wherein, Y₂ represents a sulfinyl group or a sulfonyl group; othersymbols represent the same definitions as aforementioned definitions.<Step 1B-1>

This is a step for oxidation of a compound (1f) to a compound (1g).Hydrogen peroxide, peracetic acid, methaperiodate, 3-chloroperbenzoicacid or the like can be used as an oxidizing agent. Methanol, water,dichloromethane, chloroform or the like can be used as a solvent. Thereaction can be performed for a time of 10 minutes to 30 hours at atemperature of 0° C. to reflux temperature.

[Production Method 2]

Another production method of the compound (2c), which is the compound(1c) having a halogen atom, a formyl group, or a cyano group as asubstituent at the 3-position in the indole ring

wherein, R₂₀₁ represents a halogen atom, a formyl group or a cyanogroup; other symbols represent the same definitions as theaforementioned definitions.<Step 2-1>

This is a step for obtaining a compound (2b) by the condensation of apyrimidine or pyridine derivative (1a) and a indole derivative (2a) nothaving a substituent on the 3-position. The compound (2b) can beobtained under the same conditions as <Step 1A-1>.

<Step 2-2>

This is a step in which a substituent is introduced into 3-position ofindole in a compound (2b) to obtain a compound substituted at the3-position of indole (2c). A compound (2c) substituted with a halogenatom, a formyl group, an amino group or the like as the 3-positionsubstituent can be obtained by reacting a compound (2b) withhalogenation agents such as N-chlorosuccinimide, N-bromosuccinimide or amixed reagent of phosphorous oxychloride or thionyl chloride withN,N-dimethylformamide, or after converting the compound into aN-chlorosulfonylcarbamoyl derivative by allowing chlorosulfonylisocyanate to react with the compound, followed by allowingtriethylamine to react with the derivative or the like as reported inTetrahedron 50, 6549 (1994). As a reaction solvent, 2-propanol,N,N-dimethylformamide, tetrahydrofuran, acetonitrile or the like can beused, and the reaction can be performed for a time of 10 minutes to 30hours at a temperature of 0° C. to reflux temperature.

[Production Method 3]

Another production method of the compound (1d) via the compounds (3c),(3d), (3g) or (3h)

wherein, P represents a protecting group; other symbols represent thesame definitions as in the aforementioned definitions.<Step 3-1> <Step 3-2> <Step 3-3>

These are steps for obtaining an indole derivative (3c) or an indolinederivative (3d), both being introduced a carboxamide group at the1-position, via a compound (3b) from an indole derivative (3a).

<Step 3-1> is a step for conducting carboxamidation of the 1-position ofan indole derivative (3a) to obtain a compound (3b), and can beperformed in a similar way as <Step 1A-2>. A methyl group, a benzylgroup, a substituted benzyl group, a benzyloxycarbonyl group can be usedas a protecting group, for example.

<Step 3-2> is a step for obtaining a compound (3c) by deprotecting anindole derivative (3b). Specifically, for example, in the case that Y₁is an oxygen atom, the methods used for ordinary deprotection such asdemethylation by using boron tribromide, debenzylation by usingtrifluoroacetic acid-thioanisole, debenzylation or thedebenzyoxycarbonylation by catalytic reduction can be used.

<Step 3-3> is a step for reduction of an indole derivative (3c) to anindoline derivative (3d). Catalytic hydrogenation reaction in thepresence of palladium catalyst under ordinary pressure or underpressurization or the like can be applied. Methanol,N,N-dimethylformamide, tetrahydrofuran or the like can be used as areaction solvent, and the reaction can be performed for a time of 10minutes to 30 hours at a temperature of 0° C. to reflux temperature.

<Step 3-4> <Step 3-5> <Step 3-6>

These are steps for obtaining an aminoindole derivative (3g) or anaminoindoline derivative (3h) having a carboxamide group at the1-position via a compound (3f) from a nitroindole derivative (3e).

<Step 3-4> is a step conducting carboxamidation of the 1-position of aindole derivative (3e) to obtain a compound (3f), and can be performedin the same way as in <Step 1A-2>.

<Step 3-5> is a step for reducing a nitroindole derivative (3f) to anaminoindole derivative (3g). The conditions used for reduction reactionof a nitro group to an amino group generally utilized, specifically, forexample, reduction by iron-ammonium chloride or iron-acetic acid or thelike, catalytic reduction by palladium hydroxide-hydrogen or the likecan be applied. Methanol, ethanol, water, N,N-dimethylformamide,tetrahydrofuran or the like can be used as a reaction solvent, and thereaction can be performed at a temperature of room temperature to refluxtemperature for 10 minutes to 30 hours.

<Step 3-6> is a step for reducing an indole derivative (3g) to anindoline derivative (3h) and can be performed in the same way as in<Step 3-3>.

<Step 3-7> <Step 3-8>

These are steps for condensing an indole derivative (3c or 3g) or anindoline derivative (3d or 3h) and a compound (1a) to obtain an indolederivative (1d) or an indoline derivative (3i), and can be performed inthe same way as in <Step 1A-1>.

<Step 3-9>

This is a step for oxidizing an indoline derivative (3i) to an indolederivative (1d). For example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ) or the like can be used as an oxidizing agent, and 1,4-dioxane,toluene, benzene or the like can be used as a solvent. Alternatively, amethod in which manganese acetate(III) is used as an oxidizing agent orthe like as reported in Tetrahedron Lett. 29, 2151 (1988) can beapplied.

In addition, in the case that Y₁ is the formula —NR_(Y1)— and R_(Y1) isa hydrogen atom in compounds (3g), (3h), (3c) or (3d), a compound (1d),wherein Y₁ is the formula —NR_(Y1)— and R_(Y1) is a C₁₋₆ alkyl group,can be also obtained by converting the hydrogen atom into a C₁₋₆ alkylgroup by a reductive amination reaction with aldehyde or ketone, and byusing these for the respective following reactions. In addition, in thecase that Y₁ is the formula —NR_(Y1)— and R_(Y1) is a hydrogen atom incompounds (3i) or (1d), the compounds can be also similarly convertedinto the compounds (3i) or (1d), wherein Y₁ is the formula —NR_(Y1)— andR_(Y1) is a C₁₋₆ alkyl group. In this case, sodium cyanoborohydride,sodium trimethoxyborohydride, sodium triacetoxyborohydride or the likecan be used as a reducing agent, and methanol, tetrahydrofuran,dichloromethane, dichloroethane or the like can be used as a reactionsolvent. In addition, a method in which a benzotriazole derivative isprepared and is reduced by sodium borohydride as reported in Tetrahedron47, 2683 (1991) or the like can be applied.[Production Method 4]

Another production method of the compound (1e)

wherein each symbol represents the same definition as the aforementioneddefinition.<Step 4-1>

This is a step for converting a compound (1c) to a compound (4a), andcan be performed in the same way as in <Step 1A-3>.

<Step 4-2>

This is a step for conducting carboxamidation of the 1-position ofindole in a compound (4a) to obtain a compound (1e), and can beperformed in the same way as in <Step 1A-2>.

It is to be noted that, as described in [Production method 1-A], asubstituent conversion can be also performed in R₂, R₉, R₁₀₁ and R₁₀₂ byproperly performing oxidation reaction, reduction reaction, reductiveamination reaction, ester formation reaction, amide formation reaction,protecting group introduction reaction, deprotection reaction,hydrolysis reaction or the like generally utilized after these steps.[Production Method 5]

Another production method of a compound (1e)

wherein, each symbol represents the same definition as theaforementioned definition.<Step 5-1>

This is a step for converting a pyrimidine or pyridine derivative (1a)into a corresponding urea derivative (5a), and can be performed in thesame way as in <Step 1A-3>.

<Step 5-2>

This is a step for obtaining a compound (1e) from a pyrimidine orpyridine derivative (5a) having urea. A method in which the sameoperations as in <Step 1A-1> and <Step 1A-2> are sequentially performed,a method in which the same operations as in <Step 2-1>, <Step 2-2> and<Step 1A-2> are sequentially performed, a method as in <Step 3-7>, amethod in which the same operations as in <Step 3-8> and <Step 3-9> aresequentially performed or the like can be applied.

It is to be noted that, as described in [Production method 1-A], asubstituent conversion can be also performed in R₂, R₉, R₁₀₁ and R₁₀₂ byproperly performing oxidation reaction, reduction reaction, reductiveamination reaction, ester formation reaction, amide formation reaction,protecting group introduction reaction, deprotection reaction,hydrolysis reaction or the like generally utilized after these steps.

[Production Method 6]

Another manufacturing method of compounds (1c), (1d), (3i)

wherein, L₂ represents a leaving group; each symbol represents the samedefinition as the aforementioned definition.<Step 6-1> <Step 6-2> <Step 6-3>

These are steps for condensing a pyrimidine or pyridine derivativehaving leaving groups L₁ and L₂ and an indole or indoline derivative. Inthese steps, it is preferable that L₁ is a substituent having higherreactivity than that of L₂. Specifically, for example, a combination ofL₁ being a nitro group and L₂ being a chlorine atom or the like comesunder the category. By using an indole derivative (1b), indolederivatives (3c), (3g) having a carboxamide group at the 1-position,indoline derivatives (3d), (3h) having a carboxamide group at the1-position, each compound (6b), (6c) and (6d) can be obtained under thesame conditions as in <Step 1A-1>.

<Step 6-4>

This is a step for conducting carboxamidation of the 1-position ofindole in a compound (6b) to obtain a compound (6c), and can beperformed in the same way as in <Step 1A-2>.

<Step 6-5>

This is a step for oxidizing an indoline derivative (6d) to an indolederivative (6c). The same method as in <Step 3-9> can be used.

<Step 6-6> <Step 6-7> <Step 6-8>

These are steps in which the leaving group L₂ of pyrimidine or pyridinederivatives (6b), (6c), or (6d) is converted into a group represented bythe formula —NHR₂, wherein R₂ represents the same definition as theaforementioned definition, to obtain compounds (1c), (1d), or (3i),respectively. For example, an ammonia-ethanol solution or acorresponding primary amine is used, and the reaction can be performedin a sealed tube for a time of 10 minutes to 100 hours at a temperatureof 60° C. to reflux temperature.

[Production Method 7]

Another production method of a compound (7j), which is the compoundrepresented by the formula (Ia), wherein Y is an oxygen atom and both 2-and 3-positions of indole (R₈, R₇) are hydrogen atoms

[Production Method 7-A]

wherein each symbol represents the same definition as the aforementioneddefinition.<Step 7A-1>

This is a step for obtaining a compound (7a) by introducing anaminophenoxy group into a compound (6a). It is preferable that in thecompound (6a), L₁ is a substituent having higher reactivity than that ofL₂. Specifically, for example, a combination of L₁ being a nitro groupand L₂ being a chlorine atom comes under the category. A compound (7a)can be obtained by using a compound (6a) and an aminophenol derivativein the same method as in <Step 1A-1>. In addition, after these compoundsare condensed by using a nitrophenol derivative in the same way as in<Step 1A-1>, a method for reducing a nitro group by catalytichydrogenation reaction using palladium catalyst or the like, or metalreduction reaction using iron-ammonium chloride, iron-acetic acid or thelike can be applied. In the reduction reaction of the nitro group,methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide or the likecan be used as a reaction solvent, and the catalytic hydrogenationreaction can be performed at ordinary pressure or under pressurization.The reaction can be performed at a temperature of room temperature toreflux temperature for 10 minutes to 30 hours.

<Step 7A-2>

This is a step for protecting amino group of a compound (7a) to obtain acompound (7b). As a protecting group, for example, a benzyloxycarbonylgroup or the like can be introduced by using a correspondingchlorocarbonate ester.

<Step 7A-3>

This is a method for obtaining a compound (7c) from a compound (7b).t-Butyl bromoacetate as a reagent, sodium hydride or the like as a base,N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide or the likeas a reaction solvent can be used. The reaction can be performed at atemperature of room temperature to reflux temperature for 10 minutes to30 hours.

<Step 7A-4>

This is a step for deprotecting a compound (7c) to obtain a compound(7d). There may be mentioned, for example, deprotection reaction by thecatalytic hydrogenation reaction of benzyloxycarbonyl group or the like.

<Step 7A-5>

This is a step for obtaining a compound (7e) by introducing acarboxamide group to a compound (7d). As a reagent, an isocyanatederivative, a carbamate derivative or the like can be used. As areaction solvent, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, toluene or the like can be used, and organic bases such astriethylamine or pyridine can be added thereto as requested. Thereaction can be performed for a time of 10 minutes to 30 hours and at atemperature of 0° C. to reflux temperature.

<Step 7A-6>

This is a step for obtaining a compound (7f) from a compound (7e) bycyclization reaction. The reaction is performed in an acidic condition,specifically, for example, in trifluoroacetic acid-trifluoroaceticanhydride or the like. The reaction can be performed for a time of 10minutes to 30 hours and at a temperature of 0° C. to reflux temperature.

<Step 7A-7> <Step 7A-8B

These are steps for converting into an indole derivative (7h) via acompound (7g) from a 3-oxoindoline derivative (7f). A 3-hydroxyindolinederivative (7g) is prepared by reduction of a carbonyl group usingsodium borohydride as a reagent, in tetrahydrofuran, methanol, ethanolor the like as a reaction solvent, thereafter a compound (7h) can beobtained by performing dehydration by using camphor sulfonic acid or thelike as a reagent, and toluene, dichloroethane or the like as a reactionsolvent.

<Step 7A-9> <Step 7A-10>

Thereafter, it is possible to lead to a step in which a compound (7j) isprepared under the same conditions in each of <Step 6-6>, <Step 1A-3>

[Production Method 7-B]

wherein, each symbol represents the same definition as theaforementioned definition.<Step 7B-1>

This is a step for obtaining a compound (7k) from a compound (5a), andcan be performed in the same way as in <Step 7A-1>.

<Step 7B-2>

This is a step for protecting an amino group of a compound (7k) toobtain a compound (71), and can be performed in the same way as in <Step7A-2>.

<Step 7B-3>

This is a method for obtaining a compound (7m) from a compound (71), andcan be performed in the same way as in <Step 7A-3>.

<Step 7B-4>

This is a step for deprotecting a compound (7m) to obtain a compound(7n), and can be performed in the same way as in <Step 7A-4>.

<Step 7B-5>

This is a step for introducing a carboxamide group to a compound (7n) toobtain a compound (7o), and can be performed in the same way as in <Step7A-5>.

<Step 7B-6>

This is a step for obtaining a cyclized compound (7p) from a compound(7o), and can be performed in the same way as in <Step 7A-6>.

<Step 7B-7> <Step 7B-8>

These are steps for converting into an indole derivative (7j) via acompound (7q) from a 3-oxoindoline derivative (7p), and can be performedin the same as in <Step 7A-7><Step 7A-8>.

[Production Method 8]

Another production method of a compound (8g), which is the compoundrepresented by the formula (Ia), wherein both 2- and 3-positions ofindole (R₈, R₇) are hydrogen atoms

[Production Method 8-A]

wherein, each symbol represents the same definition as theaforementioned definition.<Step 8A-1>

This is a coupling reaction of a compound (6a) with a nitrobenzenederivative. A compound (8a) can be obtained under the same conditions asin <Step 1A-1>.

<Step 8A-2>

This is a step for obtaining a compound (8b) from a compound (8a). Thereaction can be performed under the conditions as described inTetrahedron Lett. 39, 71 (1998). Specifically, a dimethylacetal compoundcan be derived by condensing a nitrotoluene derivative anddimethylformamide dimethylacetal in N,N-dimethylformamide at atemperature of room temperature to reflex temperature for 10 minutes to30 hours, and by sequentially performing the reaction of the compound inmethanol under acidic condition at a temperature of room temperature toreflex temperature for 10 minutes to 30 hours.

<Step 8A-3>

This is a step for reducing a compound (8b) to a compound (8c).Reduction by iron-ammonium chloride, iron-acetic acid or the like can beused. As a reaction solvent, methanol, ethanol, tetrahydrofuran,N,N-dimethylformamide or the like can be used. The reaction can beperformed at a temperature of room temperature to reflux temperature for10 minutes to 30 hours.

<Step 8A-4>

This is a step for converting a compound (8c) into a urea derivative toobtain a compound (8d), and can be performed in the same way as in <Step7A-5>. Alternatively, tetrahydrofuran or N,N-dimethylformamide is usedas a reaction solvent, for example, after a carbamate derivative isprepared by using phenyl chlorocarbonate or the like, and urea can bealso introduced by allowing the derivative to react with an amine at atemperature of room temperature to reflux temperature for 10 minutes to30 hours, while N,N-dimethylformamide, dimethyl sulfoxide are used as areaction solvent.

<Step 8A-5>

This is a step for cyclizing a compound (8d) to obtain a compound (8e).The reaction can be performed under the conditions as described inTetrahedron Lett. 39, 71 (1998). Specifically, there may be mentioned amethod in which reflux is performed in solvents such as benzene in thepresence of catalytic amounts of camphor sulfonic acid and quinoline.

<Step 8A-6>

This is a step for obtaining a compound (8f) from a compound (8e), andcan be performed in the same way as in <Step 6-6>.

<Step 8A-7>

This is a step for obtaining a compound (8g) from a compound (8f), andcan be performed in the same way as in <Step 7A-10>.

[Production Method 8-B]

wherein, each symbol represents the same definition as in theaforementioned definition.<Step 8B-1>

This is a step for obtaining a compound (8h) by performing couplingreaction of a compound (1a) with a nitrobenzene derivative, and can beperformed in the same way as in <Step 1A-1>.

<Step 8B-2>

This is a step for introducing urea to a compound (8h) to obtain acompound (8i), and can be performed in the same way as in <Step 1A-3>.

<Step 8B-3>

This is a step for condensing a nitrotoluene derivative (8i) anddimethylformamide dimethylacetal, subsequently, for deriving thecompound to dimethylacetal compound (8j). The step can be performed inthe same way as in <Step 8A-2>.

<Step 8B-4>

This is a step for reducing a nitro group of a compound (8j) to obtain acompound (8k), and can be performed in the same way as in <Step 8A-3>.

<Step 8B-5>

This is a step for obtaining a compound (81) from a compound (8k) byintroducing urea, and can be performed in the same way as in <Step8A-4>.

<Step 8B-6>

This is a step for cyclizing a compound (81) to obtain a compound (8g),and can be performed in the same way as in <Step 8A-5>.

[Production Method 9]

Another production method of a compound (7j)

[Production method 9-A]

wherein, each symbol represents the same definition as theaforementioned definition.<Step 9A-1>

This is a step for obtaining a compound (9a) by coupling of a compound(6a) with a phenol derivative. Specifically, for example, acorresponding condensed compound can be obtained under the sameconditions as in <Step 1A-1>, by using 4-amino-3-iodophenol obtainedfrom t-butyl(2-iodo-4-((triisopropylsilyl)oxy)phenyl)carbamate obtainedby a method as described in J. Org. chem., 62, 6507 (1997) by allowingn-butylammonium fluoride or the like to react therewith.

<Step 9A-2>

This is a step for converting a compound (9a) into a urea derivative toobtain a compound (9b), and can be performed in the same way as in <Step8A-4>.

<Step 9A-3>

This is a step for obtaining an acetylene derivative (9c) from an iodocompound (9b) using trimethylsilylacetylene. The condensation can beperformed in the presence of tetrakis(triphenylphosphine)palladium ordichlorobis(triphenylphosphine)palladium, cuprous iodide.N,N-dimethylformamide or the like can be used as a reaction solvent, andthe reaction can be performed at a temperature of room temperature toreflux temperature for 10 minutes to 30 hours.

<Step 9A-4>

This is a step for performing cyclization by heating an acetylenederivative (9c) in the presence of cuprous iodide to obtain an indolederivative (7h). N,N-dimethylformamide or the like can be used as areaction solvent, and the reaction can be performed at a temperature of80° C. to reflux temperature for 5 minutes to 10 hours.

Subsequently, a compound (7h) can be converted into a compound (7j) asdescribed in <Step 7A-9>, <Step 7A-10>.

[Production Method 9-B]

wherein each symbol represents the same definition as in theaforementioned definition.<Step 9B-1>

This is a step for coupling a compound (5a) with a phenol derivative toobtain a compound (9d), and can be performed in the same way as in <Step9A-1>.

<Step 9B-2>

This is a step for converting a compound (9d) into a urea derivative toobtain a compound (9e), and can be performed in the same way as in <Step7A-5>.

<Step 9B-3>

This is a step for obtaining an acetylene derivative (9f) from an iodocompound (9e) by using trimethylsilylacetylene, and can be performed inthe same way as in <Step 9A-3>.

<Step 9B-4>

This is a step for cyclizing an acetylene derivative (9f) by heating inthe presence of cuprous iodide to obtain an indole derivative (7j). Thesame conditions as in <Step 9A-4> can be applied.

[Production Method 10]

A typical production method of a compound (10g), which is the compoundrepresented by the formula (Ia), wherein Y is an oxygen atom, a sulfuratom or a group represented by the formula —NR_(Y)— (wherein R_(Y)represents a hydrogen atom or a C₁₋₆ alkyl group), X₁ is a grouprepresented by the formula —C(CN)═, X₂ is a group represented by theformula —CH═, R₂ is a hydrogen atom, R₃ is a hydrogen atom, anoptionally substituted C₁₋₆ alkyl group or an optionally substitutedC₃₋₈ cycloalkyl group

wherein, X₂₀₁ represents a chlorine atom or a bromine atom, X₂₀₂represents a bromine atom or an iodine atom; R₃₀₁ represents a hydrogenatom, an optionally substituted C₁₋₆ alkyl group, or an optionallysubstituted C₃₋₈ cycloalkyl group; it is preferable that as acombination of X₂₀₁ and X₂₀₂, X₂₀₂ is an iodine atom or a bromine atomif X₂₀₁ is a chlorine atom, X₂₀₂ is an iodine atom if X₂₀₁ is a bromineatom; other symbols represent the same definition as the aforementioneddefinition.<Step 10-1>

This is a step for bromination or iodination of the 5-position of a2-aminopyridine derivative (10a) having a chlorine atom or a bromineatom at the 4-position to obtain a compound (10b). For example,halogenation agents such as iodine, N-bromosuccinimide, bromine,N-iodosuccinimide can be used. As a reaction solvent, for example,N,N-dimethylformamide, dimethyl sulfoxide, methylene chloride andacetonitrile can be used. The reaction can be performed at a temperatureof 0° C. to reflux temperature for 10 minutes to 48 hours.

<Step 10-2>

This is a step for converting X₂₀₂ of a compound (10b) into a cyanogroup to obtain a compound (10c).

For example, 0.5 to 0.6 equivalent of zinc cyanide, 1.0 to 1.2equivalent of potassium cyanide, or trimethylsilylcyanide is reactedwith a compound (10b) in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium ordichlorobis(triphenylphosphine)palladium. As a reaction solvent, forexample, N,N-dimethylformamide, dioxane and tetrahydrofuran can be used.The reaction can be performed at a temperature of room temperature toreflux temperature for 10 minutes to 10 hours.

<Step 10-3> <Step 10-4> <Step 10-5>

These are steps for condensing a pyridine derivative (10c) and an indoleor indoline derivative. Compounds (10d), (10e) and (10f) can beobtained, respectively, by using an indole derivative (1b), indolederivatives (3c), (3g) having a carboxamide group at the 1-position, andindoline derivatives (3d), (3h) having a carboxamide group at the1-position under the same conditions as in <Step 1A-1>.

<Step 10-6>

This is a step for conducting carboxamidation of 1-position of indole ofa compound (10d) to obtain a compound (10e), and can be performed in thesame way as in <Step 1A-2>.

<Step 10-7>

This is a step for oxidizing an indoline derivative (10f) to an indolederivative (10e), and can be performed in the same way as in <Step 3-9>.

<Step 10-8>

This is a step for converting a compound (10e) into a compound (10g),and can be performed in the same way as in <Step 1A-3>.

[Production Method 11]

Another production method of a compound (10g)

wherein each symbol represents the same definition as the aforementioneddefinition.<Step 11-1> <Step 11-2>

These are steps for converting aminopyridine derivatives (10c), (10a)into corresponding urea derivatives (11e), (11c), respectively, and canbe performed in the same way as in <Step 1A-3>.

<Step 11-3>

This is a step for iodination or bromination of the 5-position of a2-ureidopyridine derivative (11c) having a chlorine atom or a bromineatom at the 4-position to obtain a compound (11d), and can be performedin the same way as in <Step 10-1>.

<Step 11-4>

This is a step for converting X₂₀₂ of a compound (11d) into a cyanogroup to obtain a compound (11e), and can be performed in the same wayas in <Step 10-2>.

<Step 11-5>

This is a step for obtaining a compound (10g) from a pyridine derivative(11e) having urea, and can be performed in the same way as in <Step5-2>.

[Production Method 12]

A production method of a compound (12b), which is the compoundrepresented by the formula (Ia), wherein Y is a sulfinyl group or asulfonyl group, X₁ is a group represented by the formula —C(CN)═, and R₂is a hydrogen atom

wherein other symbols represent the same definitions as theaforementioned definitions.<Step 12-1>

This is a step for oxidizing a compound (12a) to a compound (12b), andcan be performed in the same way as in <Step 1B-1>.

[Production Method 13]

A production method of a compound (131), which is the compoundrepresented by the formula (Ia), wherein Y is an oxygen atom, a sulfuratom or the formula —NR_(Y)— (wherein R_(Y) represents a hydrogen or aC₁ to C₆ alkyl group), and X₁ is a group represented by the formula—C(CN)═

wherein, X₂₀₃ represents a chlorine atom, a bromine atom or an iodineatom; other symbols represent the same definition as the aforementioneddefinition.<Step 13-1>

This is a step for converting X₂₀₃ of 4,6-dihalogenated nicotinic acidor its analogous compound (13a) such as 4,6-dichloronicotinic acid asreported in Acad. Nauk Ukr. SSSR, 1986, page 36 into an amino group toobtain a compounds (13b). The reaction can be performed at a temperatureof 0° C. to reflux temperature for 10 minutes to 100 hours by using, forexample, an ammonia-ethanol solution or the like.

<Step 13-2>

This is a step for obtaining a compound (13c) by converting a carboxylgroup of a compound (13b) into a carbamoyl group. For example, a methodin which, after oxalyl chloride or thionyl chloride is allowed to reactwith the compound at a temperature of 0° C. to reflux temperature for 10minutes to 24 hours, ammonia is allowed to react with the compound, or amethod in which diethylcyanophosphate, ammonium chloride, triethylamineare employed as disclosed in Synthesis [SYNTBF], 1998, 1467-1475 or thelike can be used.

<Step 13-3> <Step 13-4> <Step 13-5>

These are steps for condensing a pyridine or pyrimidine derivative (13c)and an indole or indoline derivative. Compounds (13d), (13e), (13f) canbe obtained, respectively, by using an indole derivative (1b), indolederivatives (3c), (3g) having a carboxamide group at the 1-position, orindoline derivatives (3d), (3h) having a carboxamide group at the1-position under the same conditions as in <Step 1A-1>.

<Step 13-6> <Step 13-11>

These are steps for conducting carboxamidation of the 1-position ofindole of compounds (13d), (13g) to obtain compounds (13e), (13j) andcan be performed in the same way as in <Step 1A-2>.

<Step 13-8> <Step 13-12> <Step 13-15>

These are steps for converting a carbamoyl group of compounds (13d),(13h), (13k) into a cyano group to obtain compounds (13g), (131). Forexample, a method in which phosphorus oxychloride, thionyl chloride,trifluoroacetic anhydride are allowed to react with the compounds at atemperature of 0° C. to reflux temperature for 10 minutes to 24 hourscan be used.

<Step 13-9> <Step 13-10> <Step 13-14>

These are steps for converting aminopyridine or aminopyrimidinederivatives (13e), (13f), (13j) into corresponding urea derivatives(13h), (13i), (13l), and can be performed in the same way as in <Step1A-3>.

<Step 13-7> <Step 13-13>

These are steps for oxidizing indoline derivatives (13f), (13i) toindole derivatives (13e), (13k), and can be performed in the same way asin <Step 3-9>.

[Production Method 14]

A typical production method of compounds (14d), (14e), (14f) byhalogenation of compounds (14a), (14b), (14c)

wherein, each symbol represents the same definition as theaforementioned definition.<Step 14-1> <Step 14-2> <Step 14-3>

These are steps for substituting a substituent in 6-membered heterocyclefrom a hydrogen atom to a halogen atom. A compound can be obtained froma corresponding compound respectively: a compound (14d) from a compound(14a), a compound (14e) from a compound (14b) and a compound (14f) froma compound (14c) as in <Step 10-1>.

[Production Method 15]

A typical production method of compounds (15a), (15b), (15c) bysubstituting a halogen atom in 6-membered heterocycle of compounds(14d), (14e), (14f) to a cyano group

wherein, each symbol represents the same definition as theaforementioned definition.<Step 15-1> <Step 15-2> <Step 15-3>

These are steps for obtaining a compound from a corresponding compoundrespectively: a compound (15a) from a compound (14d), a compound (15b)from a compound (14e) and a compound (15c) from a compound (14f) bysubstituting a substituent in 6-membered heterocycle from a halogen atomto a cyano group. 0.5 to 2.0 equivalent of zinc cyanide or 1.0 to 3.0equivalent of copper(I) cyanide, potassium cyanide, sodium cyanide,trimethylsilylcyanide or the like to compounds (14d), (14e) and (14f)can be used. In order to accelerate the reaction, as a catalyst, forexample, a palladium catalyst such astetrakis(triphenylphosphine)palladium ordichlorobis(triphenylphosphine)palladium, copper(I) iodide, copper(O) orthe like can be used. As a reaction solvent, for example,N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane,tetrahydrofuran or the like can be used. The reaction can be performedat a temperature of room temperature to reflux temperature for 10minutes to 2 days.

After completing the aforementioned reactions, purification can beperformed by an ordinary treatment method, for example, columnchromatography using silica gel or adsorbent resins or the like, orrecrystallization from a suitable solvent.

The compounds of the invention, salts thereof or hydrates of theforegoing may be formulated as tablets, powders, fine particles,granules, coated tablets, capsules, syrups, lozenges, inhalants,suppositories, injections, ointments, eye salves, eye drops, nasaldrops, ear drops, paps, lotions and the like, by any common methods. Theformulation may employ any commonly used excipients, binders,lubricants, coloring agents, corrective coatings, and if necessary,stabilizers, emulsifiers, absorbefacients, surfactants, pH adjustors,preservatives, antioxidants, or the like, in combination with variouscomponents that are ordinarily used as raw materials for pharmaceuticalformulations. For example, an oral formulation may be prepared bycombining a compound of the invention or pharmacologically acceptablesalt thereof with an excipient, if necessary adding a binder,disintegrator, lubricant, coloring agent, corrective coating or thelike, and forming a powder, fine particles, granules, tablets, coatedtablets, capsules, etc. by a common method. As such components there maybe mentioned animal and vegetable oils such as soybean oil, beef tallowand synthetic glycerides; hydrocarbons such as liquid paraffin, squalaneand solid paraffin; ester oils such as octyldodecyl myristate andisopropyl myristate; higher alcohols such as cetostearyl alcohol andbehenyl alcohol; silicone resins; silicone oils; surfactants such aspolyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerinfatty acid esters, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene hydrogenated castor oil andpolyoxyethylene-polyoxypropylene block copolymer; water-soluble polymerssuch as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer,polyethylene glycol, polyvinylpyrrolidone and methylcellulose; loweralcohols such as ethanol and isopropanol; polyhydric alcohols such asglycerin, propylene glycol, dipropylene glycol and sorbitol; sugars suchas glucose and sucrose; inorganic powders such as silicic acidanhydride, magnesium aluminum silicate and aluminum silicate, purifiedwater, and the like. Examples of excipients which may be used includelactose, corn starch, white soft sugar, glucose, mannitol, sorbit,crystalline cellulose and silicon dioxide, examples of binders which maybe used include polyvinyl alcohol, polyvinyl ether, methylcellulose,ethylcellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropylmethylcellulose, hydroxypropylcellulose,polyvinylpyrrolidone, polypropylene glycol/polyoxyethylene block polymerand meglumine, examples of disintegrators which may be used includestarch, agar, gelatin powder, crystalline cellulose, calcium carbonate,sodium bicarbonate, calcium citrate, dextrin, pectin andcarboxymethylcellulose calcium, examples of lubricants which may be usedinclude magnesium stearate, talc, polyethylene glycol, silica andhydrogenated vegetable oils, examples of coloring agents which may beused include those approved for addition to drugs, and examples ofcorrective coatings which may be used include cocoa powder, menthol,aromatic powders, mentha oil, borneol and powdered cinnamon. The tabletsor granules may also be sugar coated or provided with another type ofsuitable coating if necessary. For preparation of a liquid formulationsuch as a syrup or injection, a common method may be used to formulate acompound of the invention or a pharmacologically acceptable salt thereofwith a pH adjustor, solubilizer, isotonizing agent or the like, as wellas a solubilizing aid, stabilizer etc. if necessary. There are noparticular restrictions on the method of preparing an external agent,and any common method may be employed. That is, it may be prepared usingas base materials any of various raw materials which are ordinarily usedin drugs, quasi drugs, cosmetics and the like. As examples of specificbase materials there may be mentioned raw materials such as animal andvegetable oils, mineral oils, ester oils, waxes, higher alcohols, fattyacids, silicone oils, surfactants, phospholipids, alcohols, polyhydricalcohols, water-soluble polymers, clay minerals, purified water and thelike, and if necessary pH adjustors, antioxidants, chelating agents,antiseptics and fungicides, coloring agents, aromas and the like mayalso be added, although the base materials for external agents accordingto the invention are not limited to these. If necessary, there may alsobe included components such as ingredients havingdifferentiation-inducing activity, circulation promoters, microbicides,antiphlogistic agents, cell activators, vitamins, amino acids,humectants, keratolytic agents and the like. The amounts of theaforementioned base materials may be the concentrations established forpreparation of ordinary external agents.

There are no particular restrictions on the compound of the invention,the salt thereof or the hydrate thereof when administered, and eitheroral or parenteral administration may be carried out according toordinary methods. For example, it may be prepared and administered inthe form of a tablet, powder, a granule, a capsule, syrup, lozenge,inhalant, suppository, injection, ointment, eye salve, eye drop, nasaldrop, ear drop, pap, lotion or the like.

Although the dosage of a drug according to the invention will differdepending on severity of symptoms, age, gender, body weight, form ofadministration, type of disease, etc., it will be generally 100 μg-10 gper day for an adult and such dosages may be administered once ordivided over several.

The administration form of the medicine according to the presentinvention is not particularly restricted, and can be an oraladministration or a parenteral administration by a generally employedmethod.

The biochemical activity and actions and effects (angiogenesisinhibition activity, antitumor activity or the like) as a medicine ofthe compounds according to the present invention can be evaluated by thefollowing methods.

The following is a list of abbreviations used in the pharmacologicaltest examples described below.

-   <List of Abbreviations>-   DNA (deoxyribonucleic acid)-   VEGFR2 (vascular endothelial growth factor receptor 2)-   Hepes (N-[2-Hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid],    HEPES (buffer solution))-   MgCl₂ (Magnesium Chloride)-   MnCl₂ (Manganese Chloride)-   Na₃VO₄ (Sodium Orthovanadate(V))-   ATP (Adenosine 5′-Triphosphate)-   EDTA (Ethylenediaminetetraacetic acid)-   HTRF (Homogenous Time-Resolved Fluorescence)-   FGFR1 (Fibroblast growth factor receptor 1)-   PDGFRβ (Platelet derived growth factor receptor β)-   HGFR (Hepatocyte growth factor receptor)-   EGFR (Epidermal growth factor receptor)-   Tris (Tris(hydroxymethyl)aminomethane, Tris (buffer solution))-   NaCl (sodium Chloride)-   BSA (Bovine Serum Albumin)-   HRP (Horseradish peroxidase)-   EGTA (Ethylene glycol bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic    acid)-   SDS (Sodium Dodecylsulphate)-   NP-40 (Nonidet P-40)-   PCR: polymerase chain reaction-   RT-PCR: reverse transcription-polymerase chain reaction-   RNA: ribonucleic acid-   cDNA: complementary DNA-   cRNA: complementary RNA-   dNTP: a mixture composed of dATP, dCTP, dGTP, and dTTP-   UTP: Uridine 5′-triphosphate-   CTP: Cytidine 5′-triphosphate-   dATP: 2′-Deoxyadenosine 5′-triphosphate-   dCTP: 2′-Deoxycytidine 5′-triphosphate-   dGTP: 2′-Deoxyguanosine 5′-triphosphate-   dUTP: 2′-Deoxyuridine 5′-triphosphate-   GAPDH: glyceraldehyde 3-phosphate dehydrogenase-   FBS: Fetal bovine serum-   PBS: Phosphate buffered saline-   MTT: (3-[4,5-Dimethylthiozol-2-yl]-2,5-diphenyltetrazolium bromide;    Thiazolyl blue)-   DMSO: Dimethyl sulfoxide-   PDGF: Platelet derived growth factor-   EGF: Epidermal growth factor-   FGF2: Fibroblast growth factor 2-   VEGF: Vascular endothelial growth factor-   HGF: Hepatocyte growth factor-   TNF-α Tumor Necrosis factor alpha-   FCS: Fetal Calf Serum-   EGM-2: Endothelial Cell Growth Medium-2

PHARMACOLOGICAL TEST EXAMPLE 1 Inhibition Against Sandwich TubeFormation by Vascular Endothelial Cells in Response to Stimulation byAngiogenesis Factor

Human Umbilical Vein Endothelial Cells (HUVECs) were isolated accordingto a reported method (Shinseikagaku Jikken Koza [New BiochemistryExperiment Lectures], “Saibo Baiyo Gijutsu” [Cell Culturing Techniques],p. 197-202),

and were cultured in a 5% CO₂ incubator (37° C.) using EGM-2 medium(purchased from Clonetics Corp.) until the cells reached confluency.

An ice-cooled mixture of collagen: 5×RPMI 1640: reconstitution buffer(all purchased from Nitta Gelatin, Inc.) at 7:2:1 was dispensed at 0.4ml into each well of a 24-well plate. After the solution was gelled bybeing stationed for 40 minutes in a 5% CO₂ incubator (37° C.), HUVECcell suspension was added at 0.4 ml to each well (using 1 to 1.2×10⁵cells, though the numbers of cells differ slightly according to theHUVEC lot), the HUVEC cell suspension being in human endothelial serumfree medium (SFM, purchased from GIBCO BRL) containing addedangiogenesis factors [20 ng/ml FGF2 (purchased from GIBCO BRL) and 10ng/ml EGF (purchased from GIBCO BRL), or 25 ng/ml VEGF (purchased fromWako Pure Chemical Industries Co., Ltd.) and 10 ng/ml EGF, or 30 ng/mlHGF (purchased from R&D Co.) and 10 ng/ml EGF], and cultured overnightin a 5% CO₂ incubator (37° C.). On the following day, the medium on theupper layer was aspirated off, and then 0.4 ml of an ice-cooled mixtureof collagen: 5×RPMI 1640: reconstitution buffer (all purchased fromNitta Gelatin, Inc.) at 7:2:1 was superposed into each well prior tostationing for 4 hours in a 5% CO₂ incubator (37° C.) for gelling. Afteradding 1.5 ml of an SFM solution containing each of the aforementionedangiogenesis factors and a diluted test substance onto the upper layer,culturing was performed in a 5% CO₂ incubator (37° C.). Upon aspiratingoff the culture supernatant in each well on the 4th day after additionof the test substance, 0.4 ml of a 3.3 mg/ml MTT solution dissolved inPBS (purchased from Sigma Corp.) was added to each well and culturingwas performed for approximately 2 hours in a 5% CO₂ incubator (37° C.).The tubes formed in the collagen gel of each well were stained by MTT,the tube images were loaded into a computer (Macintosh), and the totallength of the tubes was determined by image analysis software “MacScope”(purchased from Mitani Corp.). The ratio of the total length of thetubes formed in the well containing the test substance with respect tothe total length of the tubes formed in the well containing no testsubstance was expressed as a percentage, and the concentration of eachtest substance required for 50% inhibition of tube formation (IC₅₀) wasdetermined from the ratio value. The results are shown in Table 1.

TABLE 1 VEGF-stimulated FGF2-stimulated tube formation tube formationExample No. IC₅₀ (nM) IC₅₀ (nM) 39 5.1 470 41 2.1 250 46 7.0 470 47 5.8120 53 6.7 440 78 3.0 450

PHARMACEUTICAL TEST EXAMPLE 2 Measurement of Inhibition Against ReceptorTyrosine Kinase Activity

This assay is used to determine inhibition of a test substance ontyrosine kinase activity. DNA coding for the cytoplasmic domain ofVEGFR2 is obtained by total cDNA synthesis (Edwards M, InternationalBiotechnology Lab 5(3), 19-25, 1987) or by cloning. Expression in anappropriate expression system can produce a polypeptide with tyrosinekinase activity. The cytoplasmic domain of VEGFR2 obtained by expressionof recombinant protein in, for example, insect cells have been found toexhibit intrinsic tyrosine kinase activity. For VEGFR2 (GenBankAccession No. L04947), the 1.7 kb DNA fragment described by Terman etal. (Oncogene, 6(9), 1677-1683, 1991), coding for the cytoplasmicdomain, beginning with lysine 791 and including the termination codon,was isolated from a human placental cDNA library (purchased fromClontech Laboratories, Inc.) and cloned in a Baculovirus expressionvector (pFastBacHis, purchased from GIBCO BRL). The recombinantconstruct was transfected into insect cells (Spondoptea frugiperda9(Sf9)) to prepare a recombinant Baculovirus. (Instructions forpreparation and use of recombinant Baculovirus may be found in standardtexts, such as “Bac-To-Bac Baculovirus Expression System” (GIBCO BRL).)The cytoplasmic fragment starting from lysine 398 (FGFR1, GenBankAccession No. X52833), the cytoplasmic fragment starting from lysine 558(PDGFRβ, GenBank Accession No. M21616) or the cytoplasmic fragmentstarting from lysine 974 (HGFR, GenBank Accession No. J02958) may becloned and expressed by the same method for use in assays for othertyrosine kinases. EGFR was purchased from Sigma Co. (Product No.E-2645).

For expression of the VEGFR2 tyrosine kinase, Sf9 cells were infectedwith the VEGFR2 recombinant virus and collected after 48 hours. Thecollected cells were rinsed with ice-cooled phosphate buffered saline(PBS) and then resuspended using 20 ml of ice-cooled Lysis Buffer (50 mMTris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 100 mM KCl, 1 mMphenylmethylsulfonyl fluoride, 1% (v/v) NP-40) per 1.5×10^(8 cells). Thesuspension was centrifuged at 12,000 rpm for 30 minutes at 4° C. and thesupernatant was obtained. The supernatant was added to a Ni-NTA agarosecolumn (3 ml, purchased from Qiagen) equilibrated with Buffer A {20 mMTris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 500 mM KCl, 20 mM imidazole,10% (v/v) glycerol}. The column was washed with 30 ml of Buffer A, andthen with 6 ml of Buffer B {20 mM Tris-HCl (pH 8.5), 5 mM2-mercaptoethanol, 1M KCl, 10% (v/v) glycerol}, and finally with 6 ml ofBuffer A. After washing, it was eluted with 6 ml of Buffer C {20 mMTris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 100 mM KCl, 100 mM imidazole,10% (v/v) glycerol}. The eluate was placed on a dialysis membrane(purchased from Spectrum Laboratories) and dialyzed with a dialysisbuffer {20 mM Tris-HCl (pH 7.5), 10% (v/v) glycerol, 1 mMdithiothreitol, 0.1 mM Na₃VO₄, 0.1 mM EGTA}. After dialysis, it wassupplied for SDS-electrophoresis, and the recombinant protein(His6-VEGFR2, cytoplasmic domain of VEGFR2 fused with 6 histidineresidues at the N-terminus) detected at a molecular weight ofapproximately 100 kDa with Coumassie Brilliant Blue staining was assayedusing BSA (bovine serum albumin, purchased from Sigma Co.) as thestandard substance, and stored at −80° C. until use. Using the samemethod for the cytoplasmic domains of FGFR1, PDGFRβ and HGFR yieldedrespective recombinant proteins fused with 6 histidine residues at theN-terminal (His6-FGFR1, His6-PDGFRβ or His6-HGFR).

The tyrosine kinase reaction was conducted as follows. In the case ofVEGFR2, for example, 10 μl of a kinase reaction solution {200 mM Hepes(pH 7.4), 80 mM MgCl₂, 16 mM MnCl₂, 2 mM Na₃VO₄}, 250 ng of biotin-boundpoly(Glu4:Tyr1) (biotin-poly(GT), purchased from CIS Diagnostics Co.) (6μl of a 15-fold dilution with distilled water), 15 ng of His6-VEGFR2 (10μl of a 240-fold dilution with 0.4% BSA solution) and the test substancedissolved in dimethyl sulfoxide (4 μl of a 100-fold dilution with 0.1%BSA solution) were added into each well of a 96-well round-bottom plate(NUNC Co., Product No. 163320), to a total of 30 μl. Next, 10 μl of 4 μMATP (diluted with distilled water) was added prior to incubation at 30°C. for 10 minutes, and then 10 μl of 500 mM EDTA (pH 8.0) was added.

The tyrosine phosphorylated biotin-poly(GT) was measured by theHomogenous Time-Resolved Fluorescence (HTRF) method (AnalyticalBiochemistry, 269, 94-104, 1999). Specifically, the kinase reactionsolution was transferred to a 96-well black half-plate (Product No.3694, Coster, Inc.), 7.5 ng of europium cryptate-labeledanti-phosphotyrosine antibody (Eu(K)-PY20, purchased from CISDiagnostics Co.) (25 μl of a 250-fold dilution with 20 mM Hepes (pH7.0), 0.5 M KF, 0.1% BSA solution) and 250 ng of XL665-labeledstreptavidin (XL665-SA, purchased from CIS Diagnostics Co.) (25 μl of a62.5-fold dilution with 20 mM Hepes (pH 7.0), 0.5 M KF and 0.1% BSAsolution) were added thereto, the mixture was allowed to stand at roomtemperature for 30 minutes, and then the fluorescent intensity wasmeasured at 665 nm and 620 nm under irradiation with an excitationwavelength of 337 nm using a Discovery HTRF Microplate Analyzer (PackardCo.). The tyrosine phosphorylation rate for the biotin-poly(GT) wasexpressed as the delta F % value as described in the HTRF StandardExperiment Methods text by CIS Diagnostics Co. The delta F % value inthe presence of the test substance was determined as a ratio (%) withthe delta F % value with addition of His6-VEGFR2 in the absence of thetest substance defined as 100% and the delta F % value in the absence ofboth the test substance and His6-VEGFR2 defined as 0%. This ratio (%)was used to calculate the test substance concentration required for 50%inhibition of VEGFR2 kinase activity (IC₅₀).

Measurement of inhibition against FGFR1, EGFR and HGFR kinase activitywas conducted using 15 ng of His6-FGFR1, 23 ng of EGFR and 30 ng ofHis6-HGFR, respectively, according to the tyrosine kinase reaction andHTRF method described above. Measurement of inhibition against PDGFRβkinase activity was conducted using 50 ng of His6-PDGFRβ according tothe tyrosine kinase reaction described above, followed by detection oftyrosine phosphorylated biotin-poly(GT) by the following method.Specifically, the kinase reaction solution was added to a 96-wellstreptavidin-coated plate (Product No. 15129, Pierce Chemical) andincubated at room temperature for 30 minutes. After rinsing 3 times with150 μl of a rinsing solution {20 mM Tris-HCl (pH 7.6), 137 mM NaCl,0.05% Tween-20, 0.1% BSA}, 70 μl of anti-phosphotyrosine (PY20)-HRPconjugate (Product No. P-11625, Transduction Laboratories) {2000-folddilution with 20 mM Tris-HCl (pH 7.6), 137 mM NaCl, 0.05% Tween-20, 1%BSA} was added thereto and incubation was performed at room temperaturefor 1 hour. After incubation, it was rinsed 3 times with 150 μl of therinsing solution, and 100 μl of TMB Membrane Peroxidase Substrate(Product No. 50-5077-03, Funakoshi Co., Ltd.) was added to initiate thereaction. After stationing at room temperature for 10 minutes, 100 μl of1 M phosphoric acid was added to suspend the reaction, and theabsorbance at 450 nm was measured with a microplate reader (BIO KINETICSREADER EL304, Bio-Tek Instruments). The absorbance ratio in the presenceof the test substance was determined with respect to 100% as theabsorbance with addition of His6-PDGFRβ and no test substance, and 0% asthe absorbance without addition of both the test substance andHis6-PDGFRβ. This absorbance ratio was used to calculate the testsubstance concentration required for 50% inhibition of PDGFRβ kinaseactivity (IC₅₀). The results are shown in Table 2.

TABLE 2 VEGFR2 FGFR1 Example kinase kinase No. IC₅₀(nM) IC₅₀(nM) 7 8.026 11 3.0 47 18 3.0 70 28 4.5 4.1 32 9.3 16 33 7.1 12 34 8.4 22 36 3.416 37 4.8 1.2 39 4.5 6.3 40 5.7 6.9 41 6.1 3.2 43 6.4 18 44 7.7 14 46 3212 47 40 21 50 5.0 13 53 3.8 2.1 68 37 52 79 9.8 25 81 12 38 82 15 24 8814 24 104 3.9 19 116 14 87 119 21 120 139 6.3 190 206 4.1 3.5 207 4.6 12208 7.7 6.8 209 17 29 210 8.1 40 211 45 36 212 8.6 19 213 10 330

PHARMACOLOGICAL TEST EXAMPLE 3 Evaluation of In VivoAngiogenesis-Inducing Activity Using Mouse Dorsal Air Sac Model

(1) Construction of VEGF (Vascular Endothelial Growth Factor) ExpressionVector

PCR was conducted using a human placenta cDNA library (Toyobo Co., Ltd.)as the template and the SEQ ID NO:1 (5′CCGGATCCATGAACTTTCTGCTG3′) andSEQ ID NO:2 (5′GTGAATTCTGTATCGATCGTT3′) of VEGF as primers. Aftercompletion of the PCR reaction, the 5′ ends were phosphorylated and anapproximately 600 bp DNA band was separated by 1.2% agarose gelelectrophoresis. After polymerization by self-ligation, the cDNA was cutwith EcoRI and BamHI and inserted into the EcoRI and BamHI sites ofvector pUC19. This was used to transform E. coli JM83, and plasmids wererecovered from the transformed clones. A VEGF cDNA fragment was cut outof the plasmids with HindIII and EcoRI and then inserted intopIRES2-rsGFP vector to yield pIRES2-rsGFP/VEGF for protein expression.

(2) Preparation of VEGF High-Expressing Strain

After overnight culturing of KP-1 human pancreatic cancer cells (3×10⁶cells) with 10% FCS-containing RPMI 1640 medium, an EffecteneTransfection Reagent Kit (Qiagen) was used for introduction of 3 μg ofpIRES2-rsGFP/VEGF into the KP-1 cells. After culturing in 10%FCS-containing RPMI 1640 medium containing 600 μg/ml of Geneticin,drug-resistant cells were selected. Furthermore, GFP high-expressingcells were collected by cell sorter (Becton Dickinson) as VEGFhigh-expressing KP-1 cells (KP-1/VEGF).

(3) Measurement of VEGF Level in Culture Supernatant

The KP-1/VEGF cells were prepared to 5×10⁵ cells/ml, and 0.5 ml thereofwas dispensed into each well of a 24-well plate and cultured at 37° C.for 24 hours. The culture supernatants were collected and the VEGFlevels thereof measured using a VEGF measuring kit (IBL Co., Ltd.) forconfirmation of high expression.

(4) Evaluation of In Vivo Angiogenesis-Inducing Activity Using MouseDorsal Air Sac Model

Millipore rings (Nihon Millipore) were sealed with 0.45 μm Duraporefilter membranes (Nihon Millipore) to create chambers. KP-1/VEGF humanpancreatic cancer cells (3×10⁶) suspended in 0.17 ml of collagen gelwere injected into each chamber through the injection port, and thechambers were sealed. Approximately 10 ml of air was then injected inthe dorsal skin of 6-week-old C57BL/6N female mice under anesthesia toproduce pouches, and the prepared chambers were transplanted therein.About 6 hours after completing transplantation, a test substancesuspended in 0.5% methyl cellulose was orally administered (0.1 ml/10 gbody weight), and this was continued once a day for the next 4 days.

On the 4th day after transplanting the chambers, 0.2 ml of ⁵¹Cr(Amersham Pharmacia)-labeled mouse erythrocytes (2.5×10⁶ cpm/ml) wereinjected through the caudal veins of each of the mice with thetransplanted chambers. After a prescribed period, the skin in contactwith the chamber was excised and frozen, the section in direct contactwith the chamber was precisely cut off, and the radioactivity wasmeasured with a γ-counter. The blood volume was calculated from theradioactivity and used as an index of the in vivo angiogenesis-inducingactivity. The angiogenesis volume was recorded as this measured bloodvolume minus the blood volume obtained with transplantation of a chambercontaining only collagen gel. The experiment was conducted using 10 micein the control (solvent-administered) group and 5 mice in eachcompound-administered group. The proportions (%) of the angiogenesisamount after administering a test substance to that of control are shownin Table 3.

TABLE 3 Dose (mg/kg/day) Example No. 30 100 46 59.9% 43.7% 47 87.4%39.5% 53 43.3% 44.4%

PHARMACOLOGICAL TEST EXAMPLE 4 Evaluation of Antitumor Activity onKP-1/VEGF Cells in Subcutaneous Xenograft Models

VEGF high-expressing pancreatic cancer cells (KP-1/VEGF) suspended inPBS at a concentration of 1×10⁷ cells/ml were transplanted under theright flank skin of 6-week-old female Balb/c (nu/nu) mice in a volume of0.1 ml. When the tumor volume reached approximately 100 mm³, the testsubstance was orally administered twice a day over a period of 2 weekswith a schedule of 5 days per week. The test substance was suspended in0.5% methyl cellulose for an administered volume of 0.1 ml/10 g bodyweight. The tumor size was measured twice a week using a micrometercaliper. The tumor volume was determined by measuring the long and shortdiameters of the tumor with a micrometer caliper, and calculating½×(long diameter×short diameter×short diameter). The experiment wasconducted using 10 mice in the control (solvent-administered) group and5 mice in each test substance-administered group. The proportions (%) ofthe tumor volume after administering a test substance to that of controlare shown in Table 4.

TABLE 4 Dose (mg/kg/day) Example No. 6 20 60 200 46 77.7% 59.3% 60.0%36.2% 47 80.5% 64.6% 45.3% 33.6% 53 73.1% 60.4% 48.4% 37.9%

PHARMACOLOGICAL TEST EXAMPLES 5 Evaluation of Angiogenesis InhibitionActivity in Mouse Angiogenesis Model by Using Matrigel

The experiment was performed according to the method as already reportedin the method (Lab. Invest., 67(4), 519-528, 1992). Specifically, 10μg/ml of recombinant FGF-2 (purchased from Invitrogen Corporation)dissolved in PBS was added to Matrigel Matrix (purchased from BDBiosciences) to prepare 1 μg/ml. After that, a 300 μl of this mixture ofMatrigel Matrix and Recombinant FGF-2 was injected into a subcutaneoustissue on the median line of the abdomen of a 6-week-old Balb/c (nu/nu)mouse.

Subsequently, the test substance suspended in a 0.5% methyl cellulose orthe like had been orally administered in succession once a day or twicea day for 7 days.

After 7 days, the implanted Matrigel was taken out, 300 μl of water wasadded thereto, and cut into pieces with scissors. The resultantsubstance was allowed to stand at a cool dark place overnight. Afterhemoglobin in Matrigel was fully extracted, 100 μl of the supernatantobtained by centrifugation and 100 μl of Drabkin's solution (purchasedfrom Sigma Chemical Co., Ltd) were allowed to react at room temperatureat a dark place for 1 hour. After that, the absorbance of the reactionsolution was measured with wavelength of 550 nm and reference wavelengthof 660 nm. The hemoglobin quantity (g/ml) in Matrigel was calculatedfrom the calibration curve established by use of hemoglobin as astandard.

The experiment was conducted using 8 mice in the control(solvent-administered) group and 6 mice in each compound-administeredgroup.

EXAMPLES

The compounds according to the present invention can be prepared by themethods as described in the following examples, for example. These are,however, exemplary, and the compounds according to the present inventionare not limited to the specific examples mentioned below in any cases.

Example 1N1-Ethyl-5-(2-((methoxylamino)carbonyl)amino-4-pyrimidyl)oxy-1H-1-indolecarboxamide

Similarly to Production example 27-2, a crude product of phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyrimidyl)carbamate (546mg, 1.31 mmol, 56.3%) was obtained as pale brown powder fromN1-ethyl-5-(2-amino-4-pyrimidyl)oxy-1H-1-indolecarboxamide (691 mg, 2.32mmol) and phenyl chlorocarbonate. The crude carbamate product (273 mg,0.65 mmol) was dissolved in tetrahydrofuran (7.0 ml); and triethylamine(0.91 ml, 6.53 mmol) and methoxylamine hydrochloride (273 mg, 3.27 mmol)was added thereto while stirred at room temperature. After the reactionmixture was stirred overnight, the reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with waterand brine, and was dried over anhydrous sodium sulfate. The solvent wasdistilled off, and the residue was purified by silica gel columnchromatography (eluent; ethyl acetate:hexane=1:1). The crystals wereprecipitated from ethyl acetate-hexane (1:10), filtered off, and driedunder aeration to yield the title compound (52.5 mg, 0.14 mmol, 21.7%)as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.2 Hz), 3.20-3.40(2H, m), 3.68 (3H, s), 6.45 (1H, d, J=5.6 Hz), 6.67 (1H, d, J=3.6 Hz),7.09 (1H, dd, J=2.4, 8.8 Hz), 7.43 (1H, d, J=2.4 Hz), 7.54 (1H, d, J=5.6Hz), 7.89 (1H, d, J=3.6 Hz), 8.21 (1H, m), 8.26 (1H, d, J=8.8 Hz), 8.34(1H, d, J=5.6 Hz), 9.31 (1H, d, J=10.0 Hz).

The starting materials were synthesized by the following methods.

Production example 1-1 4-Chloro-6-(1H-5-indolyloxy)-2-pyrimidinamine

Sodium hydride (1.0 g, 25 mmol) was suspended in dimethyl sulfoxide (40ml) under nitrogen atmosphere, and 5-hydroxyindole (3.33 g, 25 mmol) wasgradually added while the reaction mixture was stirred at roomtemperature. After 20 minutes, 2-amino-4,6-dichloropyrimidine (3.28 g,20 mmol) was added. The reaction mixture was heated at 100° C. and wasstirred for 3 hours. After the reaction mixture was cooled to roomtemperature, the reaction mixture was partitioned between ethyl acetateand 10% aqueous ammonia solution. The organic layer was washed withwater and brine, and dried over anhydrous sodium sulfate. After thesolvent was distilled off, the residue was purified by NH silica gelcolumn chromatography (eluent; ethyl acetate:hexane=2:1). The crystalswere precipitated from ethyl acetate, filtered off, and dried underaeration to yield the title compound (1.15 g, 4.41 mmol, 22.0%) as whitecrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.09 (2H, brs), 6.07 (1H, s), 6.57 (1H,m), 6.95 (1H, dd, J=2.4, 8.8 Hz), 7.29 (1H, m), 7.37 (1H, m), 7.41 (1H,d, J=8.8 Hz), 8.28 (1H, brs).

Production example 1-2 4-(1H-5-Indolyloxy)-2-pyrimidinamine

4-Chloro-6-(1H-5-indolyloxy)-2-pyrimidinamine (1.15 g, 4.41 mmol) wasdissolved in tetrahydrofuran (50 ml)-triethylamine (3.07 ml), 10%palladium on carbon (50% wet, 500 mg) was added, and the reactionmixture was stirred overnight under hydrogen atmosphere at atmosphericpressure.

The reaction was purged with nitrogen. After methanol (50 ml) was addedand stirred, the catalyst was filtered out. The resultant solution wasconcentrated under reduced pressure, thus the title compound (826 mg,3.65 mmol, 82.8%) was obtained as pale gray powder.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.96 (2H, brs), 6.06 (1H, d, J=5.6 Hz),6.56 (1H, m), 6.97 (1H, dd, J=2.4, 8.8 Hz), 7.26-7.28 (1H, m), 7.38-7.42(2H, m), 8.08 (1H, d, J=8.8 Hz), 8.29 (1H, brs).

Production Example 1-3N1-Ethyl-5-(2-amino-4-pyrimidyl)oxy-1H-1-indolecarboxamide

Sodium hydride (157 mg, 3.93 mmol) was suspended inN,N-dimethylformamide (10 ml) under nitrogen atmosphere, and4-(1H-5-indolyloxy)-2-pyrimidinamine (826 mg, 3.65 mmol) was graduallyadded while the reaction mixture was stirred at room temperature. After10 minutes, the reaction mixture was cooled with an ice-water bath,phenyl N-ethylcarbamate (633 mg, 3.83 mmol) was added, the reactionmixture was heated to room temperature, and the solution was stirred for4 hours. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with water and brine and dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas purified by silica gel chromatography (eluent; ethylacetate:hexane=3:1 to 4:1) to yield the title compound (691 mg, 2.32mmol, 63.7%) as white powder.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.32 (3H, t, J=7.2 Hz), 3.54 (2H, m),4.94 (2H, brs), 5.50 (1H, brs), 6.11 (1H, dd, J=2.4, 5.6 Hz), 6.62 (1H,d, J=3.6 Hz), 7.09 (1H, dd, J=2.4, 8.8 Hz), 7.34 (1H, d, J=2.4 Hz), 7.46(1H, d, J=3.6 Hz), 8.11 (1H, d, J=5.6 Hz), 8.15 (1H, d, J=8.8 Hz).

Example 25-(6-(3-(3-Diethylaminopropylamino)ureido)pyrimidin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Phenyl(6-(1-methylcarbamoyl-1H-indol-5-yloxy)pyrimidin-4-yl)carbamate(161 mg, 0.400 mmol) was dissolved in N,N-dimethylformamide (1.0 ml),and 3-(diethylamino)propylamine (130 mg, 1.00 mmol) was added while thereaction mixture was stirred at room temperature. After the reactionmixture was stirred overnight, the reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with waterand brine, and dried over anhydrous sodium sulfate. The solvent wasdistilled off, and the residue was purified by NH silica gel columnchromatography (eluent; ethyl acetate:methanol=50:1). The crystals wereprecipitated from ethyl acetate-hexane, filtered off, and dried underaeration to yield the title compound (123 mg, 0.280 mmol, 70%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.0 Hz), 1.52 (2H, m),2.32-2.46 (6H, m), 2.84 (3H, d, J=3.6 Hz), 3.12 (2H, m), 6.69 (1H, d,J=3.6 Hz), 6.98 (1H, s), 7.06 (1H, dd, J=2.2, 8.8 Hz), 7.37-7.46 (2H,m), 7.88 (1H, d, J=3.6 Hz), 8.18 (1H, m), 8.27 (1H, d, J=8.8 Hz), 8.37(1H, s), 9.49 (1H, brs).

The starting materials were synthesized by the following methods.

Production Example 2-1 Phenyl N-methylcarbamate

Methylamine hydrochloride (16.9 g, 250 mmol) was dissolved inN,N-dimethylformamide (250 ml), pyridine (44 ml, 275 mmol) was addedthereto, and the reaction mixture was stirred. The reaction mixture wascooled with ice, phenyl chloroformate (35 ml, 275 mmol) was addeddropwise thereto, and the reaction mixture was then stirred at roomtemperature for 24 hours. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The obtained crystals were suspended indiethylether, diluted with hexane, filtered off, washed with thediethylether:hexane=1:1, and dried by evacuation, to yield the titlecompound (22.3 g, 147 mmol, 59.1%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.64 (3H, d, J=3.6 Hz), 7.07 (2H, d,J=8.0 Hz), 7.17 (1H, t, J=8.4 Hz), 7.35 (2H, dd, J=8.0 Hz, 8.4 Hz), 7.58(1H, d, J=3.6 Hz).

Production Example 2-2 6-(1H-Indol-5-yloxy)pyrimidin-4-ylamine

Sodium hydride (400 mg, 10.0 mmol) was suspended in dimethyl sulfoxide(20 ml) under nitrogen atmosphere, and 5-hydroxyindole (1.33 g, 10.0mmol) was gradually added while the reaction mixture was stirred at roomtemperature. After 20 minutes, 6-chloropyrimidin-4-ylamine (1.04 g, 8.00mmol) was added thereto, the reaction mixture was heated at 100° C. andstirred for 1 hour. After the reaction mixture was naturally cooled toroom temperature, the reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water and brine,and was dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the residue was purified by silica gel columnchromatography (eluent; ethyl acetate:hexane=3:1) to yield the titlecompound (1.07 g, 4.73 mmol, 59%) as a brown oil.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.54 (1H, s), 6.43 (1H, m), 6.71 (2H,brs), 6.85 (1H, dd, J=2.4, 8.8 Hz), 7.29 (1H, d, J=2.4 Hz), 7.40-7.45(2H, m), 8.06 (1H, s), 11.20 (1H, brs).

Production Example 2-35-(6-Aminopyrimidin-4-yloxy)-1H-indol-1-carboxylic acid methylamide

Sodium hydride (199 mg, 4.97 mmol) was suspended inN,N-dimethylformamide (10 ml) under nitrogen atmosphere,6-(1H-indol-5-yloxy)pyrimidin-4-ylamine (1.07 g, 4.73 mmol) synthesizedin Production example 2-2 was gradually added while the reaction mixturewas stirred at room temperature. After 30 minutes, the reaction mixturewas cooled with an ice water bath, then phenyl N-methylcarbamate (751mg, 4.97 mmol) synthesized in Production example 2-1 was added. Thereaction mixture was heated to room temperature and stirred for 1 hour.The reaction mixture was partitioned between ethyl acetate and water.The organic layer was washed with water and brine, and was dried overanhydrous magnesium sulfate. After the solvent was distilled off, theresidue was purified by silica gel column chromatography (eluent; ethylacetate) to yield the title compound (847 mg, 2.99 mmol, 63%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.0 Hz), 5.62 (1H, s),6.68 (1H, d, J=3.6 Hz), 6.77 (2H, brs), 7.04 (1H, dd, J=2.4, 9.2 Hz),7.36 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.07 (1H, s), 8.15 (1H,q, J=4.0 Hz), 8.27 (1H, d, J=9.2 Hz).

Production Example 2-4Phenyl(6-(1-methylcarbamoyl-1H-indol-5-yloxy)pyrimidin-4-yl)carbamate

5-(6-Aminopyridin-4-yloxy)-1H-indole-1-cabxylic acid methylamide (847mg, 2.99 mmol) synthesized in Production example 2-3 was dissolved inN,N-dimethylformamide (10 ml) under nitrogen atmosphere. Pyridine (0.290ml, 11.5 mmol) and phenyl chlorocarbonate (0.394 ml, 3.15 mmol) weresequentially added dropwise thereto while cooling with an ice waterbath. After the reaction mixture was stirred for 30 minutes,triethylamine (0.417 ml, 2.99 mmol) was added, and the reaction mixturewas heated to room temperature while stirred. After 30 minutes, thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with water and brine, and was dried overanhydrous magnesium sulfate. The solvent was distilled off, and then theresidue was purified by silica gel column chromatography (eluent; ethylacetate:hexane=3:1). The crystals were precipitated from ethylacetate-hexane, filtered off, and dried under aeration to yield thetitle compound (504 mg, 1.25 mmol, 42%) as white crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.05 (3H, d, J=4.8 Hz), 5.53 (1H, q,J=4.8 Hz), 6.58 (1H, d, J=4.0 Hz), 7.08 (1H, dd, J=2.4, 8.8 Hz),7.13-7.19 (2H, m), 7.23-7.29 (1H, m), 7.34 (1H, d, J=2.4 Hz), 7.36-7.44(3H, m), 7.52 (1H, s), 8.14 (1H, d, J=8.8 Hz), 8.59 (1H, s), 9.99 (1H,brs).

Example 35-(6-(((4-Hydroxypiperidin-1-yl)carbonyl)amino)pyrimidin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 2, the title compound (100 mg, 0.231 mmol, 58%) wasobtained as white powder fromphenyl(6-(1-methylcarbamoyl-1H-indol-5-yloxy)pyrimidin-4-yl)carbamate(161 mg, 0.400 mmol) and 4-hydroxypiperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.24-1.34 (2H, m), 1.64-1.73 (2H, m),2.85 (3H, d, J=4.0 Hz), 3.02-3.12 (2H, m), 3.64 (1H, m), 3.72-3.80 (2H,m), 4.69 (1H, d, J=4.0 Hz), 6.68 (1H, d, J=3.6 Hz), 7.06 (1H, dd, J=2.4,8.8 Hz), 7.20 (1H, s), 7.40 (1H, d, J=2.4 Hz), 7.88 (1H, d, J=3.6 Hz),8.17 (1H, q, J=4.0 Hz), 8.27 (1H, d, J=8.8 Hz), 8.40 (1H, s), 9.72 (1H,brs).

Example 45-(6-((4-(Pyrrolidin-1-yl)piperidin-1-yl)carbonylamino)pyrimidin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 2, the title compound (141 mg, 0.304 mmol, 76%) wasobtained as white crystals fromphenyl(6-(1-methylcarbamoyl-1H-indol-5-yloxy)pyrimidin-4-yl)carbamate(161 mg, 0.400 mmol) and 4-(1-pyrrolidynyl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.23-1.36 (2H, m), 1.63-1.70 (4H, m),1.74-1.84 (2H, m), 2.08-2.18 (1H, m), 2.42-2.50 (4H, m), 2.82-2.95 (5H,m), 3.90-3.98 (2H, m), 6.68 (1H, d, J=3.6 Hz), 7.06 (1H, dd, J=2.4, 8.8Hz), 7.20 (1H, s), 7.40 (1H, d, J=2.4 Hz), 7.88 (1H, d, J=3.6 Hz), 8.17(1H, q, J=4.0 Hz), 8.27 (1H, d, J=8.8 Hz), 8.40 (1H, s), 9.71 (1H, brs).

Example 55-(2-(3-((1R)-1-Carbamoyl-2-phenylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(104 mg, 0.200 mmol) and triethylamine (1 ml) were dissolved inN,N-dimethylformamide (3 ml), and (2R)-2-amino-3-phenylpropionamidehydrochloride (201 mg, 1.00 mmol) was added, and the reaction mixturewas stirred for 18 hours. The reaction mixture was partitioned betweenethyl acetate and the saturated aqueous solution of ammonium chloride.The organic layer was washed with water and brine, and was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified by silica gel column chromatography (eluent; ethylacetate:methanol=50:1). The crystals were precipitated from a solventmixture of ethyl acetate-hexane, filtered off, and dried under aerationto yield the title compound (77.2 mg, 0.152 mmol, 76%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.81 (1H, dd, J=8.0, 13.2 Hz), 2.84(3H, d, J=4.4 Hz), 3.01 (1H, dd, J=4.8, 13.2 Hz), 4.38 (1H, m), 6.52(1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.2 Hz), 6.86 (1H, s), 7.01-7.07(2H, m), 7.15-7.30 (5H, m), 7.37 (1H, d, J=2.4 Hz), 7.50 (1H, s), 7.88(1H, d, J=3.2 Hz), 8.02 (1H, d, J=6.0 Hz), 8.18 (1H, q, J=4.4 Hz),8.22-8.34 (2H, m), 9.11 (1H, s).

The starting material, PhenylN-(4-(1-(methylamino)carbonyl-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamate,was synthesized as follows.

Production Example 5-1N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Sodium hydride (430 mg, 10.75 mmol) was suspended inN,N-dimethylformamide (25 ml) under nitrogen atmosphere, and4-(1H-5-indolyloxy)-2-pyridinamine (2.253 g, 10.00 mmol, CAS No.417722-11-3) described in WO 02/32872 was gradually added while stirredat room temperature. After 10 minutes, the reaction mixture was cooledwith an ice water bath, and then phenyl N-methylcarbamate (1.587 g,10.50 mmol) was added. The reaction mixture was heated to roomtemperature and stirred for 2 hours. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with water and brine, and was dried over anhydrous sodiumsulfate. The solvent was removed by distilled off. The crystals wereprecipitated from ethyl acetate, filtered off, and dried under aerationto yield the title compound (2.163 g, 7.66 mmol, 76.6%) as pale browncrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.09 (3H, d, J=4.8 Hz), 4.36 (2H, m),5.49 (1H, m), 5.92 (1H, d, J=2.0 Hz), 6.30 (1H, dd, J=2.0, 6.0 Hz), 6.61(1H, d, J=3.6 Hz), 7.07 (1H, dd, J=2.4, 8.8 Hz), 7.30 (1H, d, J=2.4 Hz),7.45 (1H, d, J=3.6 Hz), 7.92 (1H, d, J=6.0 Hz), 8.17 (1H, d, J=8.8 Hz).

Production Example 5-2 phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate

N1-Methyl-5-(2-amino-pyridyl)oxy-1H-1-indolecarboxamide (2.0 g, 7.1mmol) was suspended in tetrahydrofuran (140 ml) andN,N-dimethylformamide (1.4 ml) at room temperature, and triethylamine(2.2 ml, 16 mmol) was added while stirred. The reaction mixture wascooled with an ice, and phenyl chloroformate (1.8 ml, 15 mmol) wasadded, and the reaction mixture was stirred at room temperature for 1.5hours. Phenyl chloroformate (0.5 ml) was further added, and the reactionmixture was stirred at room temperature for 0.5 hours. Brine was addedto the reaction mixture; and this was subjected to extraction with ethylacetate, washed with brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. Diethyl ether was added to theresidue, then the precipitated crystals were filtered off, washed withdiethyl ether, and dried under aeration to yield the title compound (3.3g, 6.3 mmol, 89%) as pale brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.30 (3H, d, J=4.4 Hz), 6.66 (1H, d,J=3.6 Hz), 6.95 (1H, dd, J=2.4, 6.0 Hz), 7.10 (1H, dd, J=2.4, 8.8 Hz),7.15-7.18 (4H, m), 7.27-7.31 (2H, m), 7.40-7.45 (5H, m), 7.52 (1H, d,J=2.4 Hz), 7.88 (1H, d, J=3.6 Hz), 8.17 (1H, q, J=4.4 Hz), 8.31 (1H, d,J=8.8 Hz), 8.41 (1H, d, J=6.0 Hz).

N1-methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide described inProduction example 5-1, can be also synthesized as follows.

N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

5-(2-Aminopyridin-4-yloxy)-2,3-dihydro-1H-indole-1-carboxylic acidmethylamide (40 mg, 0.14 mmol) was dissolved in acetic acid (0.9 ml),manganese(III)acetate (29 mg, 0.17 mmol) was added thereto and thereaction mixture was stirred at 70° C. for 3.5 hours.Manganese(III)acetate (29 mg, 0.17 mmol) was further added, and thereaction mixture was further stirred at 70° C. for 0.5 hours. Afternaturally cooled to room temperature, the reaction mixture waspartitioned between ethyl acetate and saturated aqueous solution ofsodium hydrogencarbonate. The organic layer was washed with brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The obtained crystals were suspended in diethyl ether:acetone=3:1, filtered off, washed with diethyl ether, and dried underaeration to yield the title compound (24 mg, 0.085 mmol, 61%) ascolorless crystals.

The starting material,5-(2-Aminopyridin-4-yloxy)-2,3-dihydro-1H-indole-1-carboxylic acidmethylamide was synthesized as follows.

Production Example 5-3 5-Benzyloxy-1H-indole-1-carboxylic acidmethylamide

Sodium hydride (2.212 g, 55.30 mmol, 60% in oil) was suspended inN,N-dimethylformamide (100 ml), 5-benzyloxyindole (10.29 g, 46.09 mmol)was added thereto while stirred at room temperature, and the reactionmixture was stirred at room temperature for 40 minutes. The reactionmixture was cooled with an ice water bath, and phenyl N-methylcarbamate(8.360 g, 55.30 mmol) was added. After the reaction mixture was stirredfor 30 minutes, the solution was stirred at room temperature for 2.5hours. After water was added to the reaction mixture and the reactionmixture was stirred at room temperature for 1 hour, the obtainedcrystals were filtered off, then these crystals were sequentially washedwith water and diethyl ether, and dried under aeration to yield thetitle compound (12.07 g, 43.06 mmol, 93.41%) as pale yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.80 (3H, d, J=4.4 Hz), 5.10 (2H, s),6.56 (1H, d, J=3.8 Hz), 6.93 (1H, dd, J=2.4, 9.0 Hz), 7.16 (1H, d, J=2.4Hz), 7.30 (1H, t, J=7.2 Hz), 7.37 (2H, t, J=7.2 Hz), 7.45 (2H, d, J=7.2Hz), 7.74 (1H, d, J=3.8 Hz), 8.00 (1H, m), 8.11 (1H, d, J=9.0 Hz).

Production Example 5-4 5-Hydroxy-2,3-dihydro-1H-indole-1-carboxylic acidmethyl amide

5-Benzyloxy-1H-indole-carboxylic acid methylamide (10.00 g, 35.67 mmol)was dissolved in methanol (200 ml) and tetrahydrofuran (150 ml), 10%palladium on carbon (0.9 g) was added, and the reaction mixture wasstirred at room temperature under hydrogen atmosphere for 9 hours. Afterthe catalyst was removed by filtration, the solvent was distilled offunder reduced pressure. The residue was dissolved in ethanol (400 ml),10% palladium on carbon (0.9 g) was added, then the reaction mixture wasstirred at room temperature under hydrogen atmosphere for 26 hours.After the catalyst was removed by filtration, the solvent was distilledoff under reduced pressure. The obtained crystals were suspended indiethyl ether, filtered off, washed with diethyl ether, and dried underaeration to yield the title compound (6.522 g, 33.93 mmol, 95.12%) asgrayish crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.61 (3H, d, J=4.4 Hz), 2.99 (2H, t,J=8.6 Hz), 3.76 (2H, t, J=8.6 Hz), 6.33 (1H, d, J=4.4 Hz), 6.43 (1H, dd,J=2.4, 8.4 Hz), 6.54 (1H, d, J=2.4 Hz), 7.58 (1H, d, J=8.4 Hz), 8.82(1H, s).

Production Example 5-55-(2-Aminopyridin-4-yloxy)-2,3-dihydro-1H-indole-1-carboxylic acidmethylamide

Sodium hydride (202 mg, 3.89 mmol, 60% in oil) was suspended in dimethylsulfoxide (5.0 ml), then 5-hydroxy-2,3-dihydro-1H-indole-1-carboxylicacid methylamide (971 mg, 5.06 mmol) and 2-amino-4-chloropyridine (500mg, 3.89 mmol) were added at room temperature under nitrogen atmosphere,and the reaction mixture was heated and stirred at 160° C. for 12 hoursunder nitrogen atmosphere. After naturally cooled down to roomtemperature, the reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with brine, was dried overanhydrous magnesium sulfate, and was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Fuji Silysia BW-300; eluent: ethyl acetate, ethylacetate:methanol=85:10 in this order). The fractions containing thedesired compound were concentrated, and the residue was further purifiedby silica gel column chromatography (Fuji Silysia NH, eluent; from ethylacetate to ethyl acetate:methanol=90:10). The obtained crystals weresuspended in diethyl ether:acetone=3:1, filtered off, washed withdiethyl ether, and dried under aeration to yield the title compound (51mg, 0.18 mmol, 4.6%) as pale green crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.65 (3H, d, J=4.4 Hz), 3.09 (2H, t,J=8.6 Hz), 3.86 (2H, t, J=8.6 Hz), 5.75 (1H, d, J=2.0 Hz), 5.85 (2H,brs), 6.07 (1H, dd, J=2.0, 6.0 Hz), 6.56 (1H, d, J=4.4 Hz), 6.81 (1H,dd, J=2.4, 8.4 Hz), 6.90 (1H, d, J=2.4 Hz), 7.73 (1H, d, J=6.0 Hz), 7.83(1H, d, J=8.4 Hz).

Example 65-(2-(3-((1S)-1-Carbamoyl-2-phenylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

N1-Methyl-5-((2-amino-4-pyridyl)oxy-1H-1-indolcarboxamide (100 mg, 0.354mmol) synthesized in Production example 5-1 and triethylamine (0.3 ml)were dissolved in N,N-dimethylformamide (3 ml). Phenyl chlorocarbonate(0.0888 ml, 0.708 mmol) was added dropwise thereto at room temperatureand the reaction mixture was stirred for 30 minutes.(2S)-2-Amino-3-phenylpropionamide (290 mg, 1.77 mmol) was added and thereaction mixture was stirred for 3 days. The reaction mixture waspartitioned between a solvent mixture of ethyl acetate-tetrahydrofuranand water. The organic layer was washed with water and brine, dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified by silica gel column chromatography (eluent; ethylacetate:methanol=20:1). The crystals were precipitated from a solventmixture of ethyl acetate-hexane, filtered off, and dried under aerationto yield the title compound (69.4 mg, 0.147 mmol, 41%) as whitecrystals.

Example 75-(2-(3-(2-Oxo-2-(pyrrolidin-1-yl)ethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

tert-Butoxycarbonylaminoacetic acid (876 mg, 5.00 mmol) andN-methylmorpholine (506 mg, 5.00 mmol) were dissolved in tetrahydrofuran(20 ml). After isobutyl chloroformate (683 mg, 5.00 mmol) was addeddropwise at below −15° C. and the reaction mixture was stirred for 30minutes, pyrrolidine (782 mg, 11.0 mmol) was added at below −15° C. andthe reaction mixture was further stirred at 0° C. for 30 minutes. Thereaction mixture was partitioned between ethyl acetate and 1N aqueoussolution of sodium hydroxide. The organic layer was washed with 1Nhydrochloric acid, a saturated aqueous solution of sodiumhydrogencarbonate and brine, and was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the obtained residue wasdissolved in a solvent mixture of ethyl acetate (10 ml)-tetrahydrofuran(5 ml). 4N hydrochloric acid Ethyl acetate solution (5 ml) was added andthe reaction mixture was stirred at room temperature for 18 hours. Afterthe solvent was distilled off, ethyl acetate was added to the crudeproduct to precipitate crystals; and the crystals were filtered off anddried under aeration to yield 2-amino-1-(pyrrolidin-1-yl)ethanonehydrochloride (573 mg, 4.16 mmol, 84%) as white crystals.

The title compound (74.7 mg, 0.171 mmol, 86%) was obtained as whitecrystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(104 mg, 0.200 mmol) synthesized in Production example 5-2 and thepreviously obtained 2-amino-1-(pyrrolidin-1-yl)ethanone hydrochloride(165 mg, 1.00 mmol) similarly to Example 5.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.71-1.81 (2H, m), 1.83-1.93 (2H, m),2.85 (3H, d, J=4.0 Hz), 3.26-3.40 (4H, m), 3.90 (2H, d, J=4.4 Hz), 6.55(1H, dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3.4 Hz), 6.94 (1H, d, J=2.0 Hz),7.06 (1H, dd, J=2.0, 9.0 Hz), 7.38 (1H, d, J=2.0 Hz), 7.89 (1H, d, J=3.4Hz), 8.05 (1H, d, J=6.0 Hz), 8.12-8.26 (2H, m), 8.30 (1H, d, J=9.0 Hz),9.28 (1H, s).

Example 85-(2-(3-(2-(4-Hydroxy-4-methylpiperidin-1-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

4-Hydoxy-4-methylpiperidine hydrochloride (113 mg, 0.745 mmol) wassuspended in N,N-dimethylformamide (3 ml), then triethylamine (1 ml) wasadded; benzotriazole-1-isooxytris(dimethylamino)phosphoniumhexafluorophosphate (201 mg, 0.454 mmol) and((4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)aceticacid (145 mg, 0.378 mmol) were added thereto; and the reaction mixturewas stirred at room temperature for 2 hours. After water was added tothe reaction mixture, extraction was performed with ethylacetate-tetrahydrofuran. The organic layer was washed with brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Fuji Silysia NH silica gel; ethyl acetate, ethyl acetate:methanol=20:1,10:1 in this order). After concentration under reduced pressure, theproduct was solidified with diethyl ether, suspended, filtered off,washed with diethyl ether, and dried under aeration to yield the titlecompound (137 mg, 0.285 mmol, 75.4%) as a colorless amorphous solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.10 (3H, s), 1.38-1.44 (4H, m), 2.83(3H, d, J=3.6 Hz), 3.02 (2H, m), 3.90 (2H, m), 3.96 (2H, d, J=4.0 Hz),4.37 (1H, s), 6.52 (1H, d, J=5.6 Hz), 6.67 (1H, d, J=3.2 Hz), 6.91 (1H,s), 7.04 (1H, d, J=9.0 Hz), 7.36 (1H, s), 7.87 (1H, d, J=3.2 Hz), 8.03(1H, d, J=5.6 Hz), 8.17 (2H, m), 8.28 (1H, d, J=9.0 Hz), 9.27 (1H, s).

The starting materials were synthesized as follows.

Production Example 8-1((4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)aceticacid

Methyl aminoacetate hydrochloride (300 mg, 2.3 mmol) was dissolved inN,N-dimethylformamide (4 ml), and then triethylamine (1 ml) was added.PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(250 mg, 0.48 mmol) synthesized in Production example 5-2 was addedthereto. The reaction mixture was stirred at room temperature for 22hours. After water was added to the reaction mixture, extraction wasperformed with a solvent mixture of ethyl acetate-tetrahydrofuran. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia BW-300, ethylacetate). The obtained pale yellow oil was dissolved in a solventmixture of tetrahydrofuran (2 ml)-methanol (1 ml), then 4N aqueoussolution of lithium hydroxide (0.48 ml) was added, and the reactionmixture was stirred at room temperature for 1 hour. After that, 1Nhydrochloric acid (2 ml) was added, and this was subjected to extractionwith ethyl acetate-tetrahydrofuran. The organic layer was washed withbrine and dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to yield the title compound (145 mg, 0.38 mmol, 79%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.83 (3H, d, J=3.6 Hz), 3.81 (2H, d,J=5.6 Hz), 6.57 (1H, m), 6.68 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.05 (1H,dd, J=2.0, 9.2 Hz), 7.38 (1H, d, J=2.0 Hz), 7.88 (1H, d, J=3.6 Hz), 8.05(1H, d, J=5.6 Hz), 8.16-8.30 (3H, m), 9.33 (1H, brs).

Production Example 8-2Benzyl(4-hydroxy-4-methylpiperidin-1-yl)carboxylate

Benzyl(4-oxopiperidin-1-yl)carboxylate (4.7 g, 20 mmol) was dissolved intetrahydrofuran (200 ml); methyllithium-diethylether solution (9.0 ml(1.02 M)+11.6 ml (1.14 M), total 22 mmol) was added dropwise thereto(internal temperature: −60° C. or below) while stirred at −78° C. undernitrogen atmosphere; and then the reaction mixture was stirred for 1.5hours as it stands. On the other hand, a similar reaction was performedby using piperidin-4-one-1-carboxylate (1.1 g, 5.0 mmol) in anothercontainer. After the saturated aqueous solution of ammonium chloride wasadded to each reaction mixture, the two reaction mixtures were mixed.Extraction was performed with ethyl acetate, washed with brine, driedover anhydrous magnesium sulfate, concentrated under reduced pressure,and purified by silica gel column chromatography (Fuji Silysia BW-300,hexane-ethyl acetate system) to yield the title compound (4.5 g, 18mmol, 73%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.10 (3H, s), 1.32-1.44 (4H, m), 3.17(2H, m), 3.61 (2H, dt, J=3.6, 9.2 Hz), 4.34 (1H, s), 5.04 (2H, s),7.27-7.37 (5H, m).

Production Example 8-3 4-Hydroxy-4-methylpiperidine monohydrochloride

Benzyl(4-hydroxy-4-methylpiperidin-1-yl)carboxylate (4.5 g, 18 mmol) wasdissolved in methanol (90 ml), 10% palladium on carbon powder (0.60 g)was added, and the reaction mixture was stirred at room temperatureunder hydrogen atmosphere overnight. The catalyst was removed byfiltration and the resultant solution was concentrated under reducedpressure to yield a crude product of 4-hydroxy-4-methylpiperidine as apale yellow oil (2.1 g). After the product was dissolved in methanol, 1Nhydrochloric acid (17.5 ml) was added and the solvent was distilled offunder reduced pressure. The obtained crystals were suspended in acetone,the crystals were filtered off, washed with acetone, and dried underaeration to yield the title compound (2.1 g, 14 mmol, 77%) as colorlesscrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.14 (3H, s), 1.55-1.69 (4H, m), 3.00(4H, m), 4.68 (1H, brs), 8.77 (1H, brs), 8.89 (1H, brs).

Example 95-(2-(3-((1S)-1-Carbamoylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

N1-Methyl-5-((2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (100 mg,0.354 mmol) synthesized in Production example 5-1 and triethylamine (1ml) were dissolved in tetrahydrofuran (3 ml), then phenylchlorocarbonate (0.0888 ml, 0.708 mmol) was added dropwise at roomtemperature, and the reaction mixture was stirred for 2 hours. After thesolvent was distilled off under reduced pressure, the residue wasdissolved in N,N-dimethylformamide (3 ml). (2S)-2-Aminopropionamidehydrochloride (220 mg, 1.77 mmol) and triethylamine (1 ml) were addedand the reaction mixture was stirred for 18 hours. The reaction mixturewas partitioned between ethyl acetate and a saturated aqueous solutionof ammonium chloride. The organic layer was washed with brine and driedover anhydrous magnesium sulfate. The solvent was distilled off and theresidue was purified by silica gel column chromatography (eluent; ethylacetate:methanol=20:1). The crystals were precipitated from a solventmixture of ethyl acetate-hexane, filtered off, and dried under aerationto yield the title compound (38.5 mg, 0.0971 mmol, 27%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.21 (3H, d, J=6.8 Hz), 2.85 (3H, d,J=4.0 Hz), 4.17 (1H, m), 6.55 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz),6.93 (1H, s), 7.02 (1H, s), 7.06 (1H, dd, J=2.0, 8.8 Hz), 7.39 (1H, d,J=2.0 Hz), 7.46 (1H, s), 7.90 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.2 Hz)8.11 (1H, brs), 8.20 (1H, q, J=4.0 Hz), 8.30 (1H, d, J=8.8 Hz), 9.21(1H, brs).

Example 105-(2-(3-((1S)-1-Carbamoyl-3-methylbutyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 9, the title compound (59.5 mg, 0.135 mmol, 38%)was obtained as white crystals fromN1-methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (100 mg, 0.354mmol) synthesized in Production example 5-1 and(2S)-2-amino-4-methylpentanamide hydrochloride (295 mg, 1.77 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.83-0.91 (6H, m), 1.35-1.50 (2H, m),1.58 (1H, m), 2.85 (3H, d, J=4.4 Hz), 4.17 (1H, m), 6.53 (1H, dd, J=2.4,6.0 Hz), 6.69 (1H, d, J=3.8 Hz), 6.92-7.01 (2H,m), 7.06 (1H, dd, J=2.4,8.8 Hz), 7.38 (1H, d, J=2.4 Hz), 7.48 (1H, s), 7.89 (1H, d, J=3.8 Hz)7.98-8.12 (2H, m), 8.19 (1H, q, J=4.4 Hz), 8.30 (1H, d, J=8.8 Hz), 9.09(1H, s).

Example 115-(2-(3-Carbamoylmethylureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (52.8 mg, 0.138 mmol, 69%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(104 mg, 0.200 mmol) synthesized in Production example 5-2 andglycinamide hydrochloride (111 mg, 1.00 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.0 Hz), 3.70 (2H, d,J=5.2 Hz), 6.53 (1H, dd, J=2.4, 5.8 Hz), 6.69 (1H, d, J=3.4 Hz), 6.92(1H, d, J=2.4 Hz), 7.01 (1H, s), 7.06 (1H, dd, J=2.4, 9.2 Hz), 7.34-7.42(2H, m), 7.89 (1H, d, J=3.4 Hz), 8.05 (1H, d, J=5.8 Hz), 8.14-8.26 (2H,m), 8.30 (1H, d, J=9.2 Hz), 9.21 (1H, s).

Example 125-(2-(3-Cyclopropylcarbamoylmethylureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (50.7 mg, 0.120 mmol, 60%)was obtained as white powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(104 mg, 0.200 mmol) synthesized in Production example 5-2 and2-amino-N-cyclopropylacetamide hydrochloride (151 mg, 1.00 mmol)obtained from tert-butoxycarbonylaminoacetic acid and cyclopropylamineby the method similar to Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.36-0.42 (2H, m), 0.57-0.63 (2H, m),2.60 (1H, m), 2.85 (3H, d, J=4.4 Hz), 3.68 (2H, d, J=5.2 Hz), 6.53 (1H,dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.91 (1H, d, J=2.0 Hz), 7.06(1H, dd, J=2.4, 9.0 Hz), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz),8.00 (1H, d, J=4.0 Hz), 8.06 (1H, d, J=6.0 Hz) 8.14-8.26 (2H, m), 8.30(1H, d, J=9.0 Hz), 9.21 (1H, s).

Example 135-(2-(3-((1S)-1-Carbamoyl-2-hydroxyethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 9, the title compound (52.1 mg, 0.126 mmol, 36%)was obtained as white crystals fromN1-methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (100 mg, 0.354mmol) synthesized in Production example 5-1 and(2S)-2-amino-3-hydroxypropionamide hydrochloride (249 mg, 1.77 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.4 Hz), 3.52 (1H, dd,J=4.8, 6.4 Hz), 3.62 (1H, dd, J=4.8, 6.4 Hz), 4.13 (1H, m), 4.94 (1H,brs), 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.99 (1H,s), 7.02-7.10 (2H, m), 7.35 (1H, s), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H,d, J=3.6 Hz), 8.05 (1H, d, J=6.0 Hz), 8.10-8.26 (2H, m), 8.30 (1H, d,J=8.8 Hz), 9.22 (1H, s).

Example 145-(2-(3-((1R)-1-Carbamoyl-2-hydroxyethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 9, the title compound (56.0 mg, 0.136 mmol, 68%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(104 mg, 0.200 mmol) synthesized in Production example 5-2 and(2R)-2-amino-3-hydroxypropioamide hydrochloride (167 mg, 1.00 mmol)obtained from (2R)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acidand aqueous ammonia by the method similar to Example 7.

Example 15(2S)-2-(3-(4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)ureido)-1,5-pentanedicarboxylicacid diamide

Similarly to Example 6, the title compound (82.5 mg, 0.189 mmol, 51%)was obtained as white powder fromN1-methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (100 mg, 0.354mmol) synthesized in Production example 5-1 and(2S)-2-amino-1,5-pentanedicarboxylic acid diamide hydrochloride (321 mg,1.77 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.66-2.28 (4H, m), 2.85 (3H, d, J=4.4Hz), 4.17 (1H, m), 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz),6.72 (1H, s), 6.97 (1H, s), 7.01-7.10 (2H, m), 7.30 (1H, s), 7.38 (1H,d, J=2.4 Hz), 7.49 (1H, s), 7.76 (1H, s) 7.89 (1H, d, J=3.6 Hz), 8.06(1H, d, J=6.0 Hz), 8.18 (1H, q, J=4.4 Hz), 8.30 (1H, d, J=8.8 Hz), 9.13(1H, s).

Example 16(2S)-2-(3-(4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)ureido)succinamide

Similarly to Example 6, the title compound (65.7 mg, 0.150 mmol, 42%)was obtained as white crystals fromN1-methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (100 mg, 0.354mmol) synthesized in Production example 5-1 and (2S)-2-aminosuccinamidehydrochloride (297 mg, 1.77 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.45 (2H, d, J=6.8 Hz), 2.85 (3H, d,J=3.6 Hz), 4.40 (1H, m), 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d,J=3.6 Hz), 6.88 (1H, s), 6.95 (1H, s), 7.00 (1H, d, J=2.4 Hz), 7.06 (1H,dd, J=2.4, 9.2 Hz), 7.28 (1H, s), 7.35 (1H, s), 7.38 (1H, d, J=2.4 Hz),7.89 (1H, d, J=3.6 Hz), 8.04 (1H, d, J=6.0 Hz), 8.18 (1H, q, J=4.0 Hz),8.26 (1H, brs), 8.30 (1H, d, J=9.2 Hz), 9.19 (1H, s).

Example 175-(2-(3-((1S)-1-Cyclopropylcarbamoyl-2-hydroxyethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (72.0 mg, 0.159 mmol, 80%)was obtained as white powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(104 mg, 0.200 mmol) synthesized in Production example 5-2 and(2S)-2-amino-N-cyclopropyl-3-hydroxypropionamide hydrochloride (181 mg,1.00 mmol) obtained from(2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid andcyclopropylamine by the method similar to Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.35-0.44 (2H, m), 0.54-0.63 (2H, m),2.62 (1H, m), 2.85 (3H, d, J=4.0 Hz), 3.45-3.58 (2H, m), 4.09 (1H, m),4.91 (1H, t, J=5.2 Hz), 6.53 (1H, dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3.6Hz), 6.99 (1H, d, J=2.0 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.38 (1H, d,J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 7.98 (1H, d, J=4.4 Hz), 8.05 (1H, d,J=6.0 Hz), 8.09-8.24 (2H, m), 8.30 (1H, d, J=8.8 Hz), 9.18 (1H, s).

Example 185-(2-(3-((1S)-1-Hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (67.6 mg, 0.145 mmol, 73%)was obtained as white powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(104 mg, 0.200 mmol) synthesized in Production example 5-2 and(2S)-2-amino-3-hydroxy-1-(pyrrolidin-1-yl)propan-1-one hydrochloride(165 mg, 0.848 mmol) obtained from(2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid andpyrrolidine by the method similar to Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.72-1.81 (2H, m), 1.81-1.90 (2H, m),2.85 (3H, d, J=4.4 Hz), 3.22-3.36 (2H, m), 3.46-3.60 (4H, m), 4.54 (1H,m), 4.98 (1H, brs), 6.54 (1H, dd, J=2.0, 5.6 Hz), 6.69 (1H, d, J=3.6Hz), 6.97 (1H, d, J=2.0 Hz), 7.05 (1H, dd, J=2.4, 8.8 Hz), 7.38 (1H, d,J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 8.05 (1H, d, J=5.6 Hz), 8.13-8.23(2H, m), 8.30 (1H, d, J=8.8 Hz), 9.18 (1H, s).

Example 195-(2-(3-((1R)-1-Hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (305 mg, 0.654 mmol, 93%) wasobtained as white powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(366 mg, 0.700 mmol) synthesized in Production example 5-2 and(2R)-2-amino-3-hydroxy-1-(pyrrolidin-1-yl)propan-1-one hydrochlorideobtained from (2R)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acidand pyrrolidine by the method similar to Example 7.

Example 205-(2-(3-((1S)-1-Hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (124 mg, 0.258 mmol, 86%) wasobtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(157 mg, 0.300 mmol) synthesized in Production example 5-2 and(2S)-2-amino-3-hydroxy-1-(piperidin-1-yl)propan-1-one hydrochloride (312mg, 1.50 mmol) obtained from(2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid and piperidineby the method similar to Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.36-1.61 (6H, m), 2.85 (3H, d, J=4.4Hz), 3.40-3.53 (6H, m), 4.76 (1H, m), 4.92 (1H, brs), 6.54 (1H, dd,J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.97 (1H, d, J=2.4 Hz), 7.06(1H, dd, J=2.4, 9.0 Hz), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz),8.05 (1H, d, J=6.0 Hz), 8.10-8.26 (2H, m), 8.30 (1H, d, J=9.0 Hz), 9.21(1H, s).

Example 215-(2-(3-((1R)-1-Hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

(2R)-2-Benzyloxycarbonylamino-3-hydroxypropionic acid (1.91 g, 8.00mmol) and N-methylmorpholine (809 mg, 8.00 mmol) were dissolved intetrahydrofuran (20 ml). After isobutyl chloroformate (1.09 g, 8.00mmol) was added dropwise at −15° C. or below, the reaction mixture wasstirred for 30 minutes. Then, pyrrolidine (1.13 g, 16.0 mmol) was addedat −15° C. or below, and the reaction mixture was further stirred at 0°C. for 30 minutes. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with 1N hydrochloricacid, 1N aqueous solution of sodium hydroxide, a saturated aqueoussolution of sodium hydrogencarbonate, and brine, and dried overanhydrous magnesium sulfate. The solvent was distilled off, and theobtained residue was dissolved in a solvent mixture of methanol (15ml)-tetrahydrofuran (15 ml). Then, 10% palladium on carbon (wet) (300mg) was added, and the reaction mixture was stirred at room temperatureunder the stream of hydrogen for 90 minutes. After the catalyst wasremoved by filtration, the solvent of the filtrate was distilled offunder reduced pressure to yield(2R)-2-amino-3-hydroxy-1-(piperidin-1-yl)propan-1-one (684 mg, 3.97mmol, 50%) as a colorless oil. Similarly to Example 5, the titlecompound (107 mg, 0.223 mmol, 74%) was obtained as white crystals fromphenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(157 mg, 0.300 mmol) synthesized in Production example 5-2 andpreviously obtained(2R)-2-amino-3-hydroxy-1-(piperidin-1-yl)propan-1-one (228 mg, 1.32mmol).

Example 225-(2-(3-((1S)-1-Hydroxymethyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (118 mg, 0.238 mmol, 69%) wasobtained as white powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(179 mg, 0.343 mmol) synthesized in Production example 5-2 and(2S)-2-amino-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-onehydrochloride (385 mg, 1.71 mmol) obtained from(2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid and4-hydroxypiperidine by the method similar to Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.16-1.40 (2H, m), 1.61-1.80 (2H, m),2.85 (3H, d, J=4.0 Hz), 2.98-3.50 (5H, m), 3.63-3.95 (3H, m), 4.76 (1H,m), 4.92 (1H, brs), 6.55 (1H, dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3.6Hz), 6.96 (1H, d, J=2.0 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.38 (1H, d,J=2.4 Hz), 7.90(1H, d, J=3.6 Hz), 8.05 (1H, d, J=6.0 Hz), 8.08-8.26 (2H,m), 8.30 (1H, d, J=8.8 Hz), 9.26 (1H, s).

Example 235-(2-(3-((1S)-1-Hydroxymethyl-2-(morpholin-4-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (121 mg, 0.251 mmol, 84%) wasobtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(157 mg, 0.300 mmol) synthesized in Production example 5-2 and(2S)-2-amino-3-hydroxy-1-(morpholin-4-yl)propan-1-one hydrochloride (316mg, 1.50 mmol) obtained from(2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid and morpholineby the method similar to Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.4 Hz), 3.36-3.62(10H, m), 4.74 (1H, m), 4.92 (1H, brs), 6.54 (1H, dd, J=2.4, 6.0 Hz),6.69 (1H, d, J=3.6 Hz), 6.96 (1H, d, J=2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8Hz), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 8.05 (1H, d, J=6.0Hz), 8.14-8.28 (2H, m), 8.30 (1H, d, J=8.8 Hz), 9.25 (1H, s).

Example 245-(2-(3-(2-Cyclopropylcarbamoylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (117 mg, 0.268 mmol, 89%) wasobtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(157 mg, 0.300 mmol) synthesized in Production example 5-2 and3-amino-N-cyclopropylpropionamide hydrochloride (247 mg, 1.50 mmol)obtained from 3-(tert-butoxycarbonylamino)propionic acid andcyclopropylamine by the method similar to Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.32-0.38 (2H, m), 0.54-0.60 (2H, m),2.19 (2H, t, J=6.4 Hz), 2.60 (1H, m), 2.85 (3H, d, J=4.4 Hz), 3.25-3.33(2H, m), 6.53 (1H, dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.90 (1H,d, J=2.0 Hz), 7.05 (1H, dd, J=2.4, 9.0 Hz), 7.38 (1H, d, J=2.4 Hz), 7.89(1H, d, J=3.6 Hz), 7.93 (1H, d, J=4.0 Hz), 7.96-8.06 (2H, m), 8.18 (1H,q, J=4.4 Hz), 8.30 (1H, d, J=9.0 Hz), 9.08 (1H, s).

Example 255-(2-(3-(3-oxo-3-(pyrrolidin-1-yl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (122 mg, 0.270 mmol, 90%) wasobtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(157 mg, 0.300 mmol) synthesized in Production example 5-2 and3-amino-1-(pyrrolidin-1-yl)propan-1-one hydrochloride (268 mg, 1.50mmol) obtained from 3-(tert-butoxycarbonylamino)propionic acid andpyrrolidine by the same method similar to Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.70-1.78 (2H, m), 1.80-1.88 (2H, m),2.40 (2H, t, J=6.2 Hz), 2.85 (3H, d, J=4.4 Hz), 3.24-3.38 (6H, m), 6.52(1H, dd, J=2.0, 5.6 Hz), 6.69 (1H, d, J=3.6 Hz), 6.92 (1H, d, J=2.0 Hz),7.05 (1H, dd, J=2.4, 9.0 Hz), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6Hz), 7.98-8.10 (2H, m), 8.18 (1H, q, J=4.4 Hz), 8.30 (1H, d, J=9.0 Hz),9.10 (1H, s).

Example 265-(2-(3-(3-(4-Hydroxy-4-methylpiperidin-1-yl)-3-oxopropyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

The title compound (177 mg, 0.358 mmol, 71.1%) was obtained as colorlesscrystals by performing the reaction similar to Example 8 using3-(3-(4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)ureido)propionicacid (200 mg, 0.503 mmol) and 4-hydroxy-4-methylpiperidinemonohydrochloride (114 mg, 0.755 mmol, Production example 8-3).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.07 (3H, s), 1.23-1.41 (4H, m), 2.44(2H, d, J=4.8 Hz), 2.83 (3H, d, J=4.4 Hz), 2.98 (1H, m), 3.23-3.30 (3H,m), 3.46 (1H, m), 3.93 (1H, m), 4.32 (1H, s), 6.49 (1H, dd, J=2.0, 6.0Hz), 6.67 (1H, d, J=3.4 Hz), 6.90 (1H, s), 7.03 (1H, dd, J=2.0, 8.8 Hz),7.35 (1H, d, J=2.0 Hz), 7.87 (1H, d, J=3.4 Hz), 8.00 (2H, m), 8.15 (1H,d, J=4.4 Hz), 8.28 (1H, d, J=8.8 Hz), 9.06 (1H,s).

The starting material was synthesized by the following methods.

Production Example 26-13-(3-(4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)ureido)propionicacid

Ethyl 4-aminopropionate hydrochloride (588 mg, 3.8 mmol) was suspendedin N,N-dimethylformamide (3.0 ml), and then 5N aqueous solution ofsodium hydroxide (0.77 ml, 3.8 mmol) was added, and the reaction mixturewas stirred at room temperature. PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(400 mg, 0.77 mmol, Production example 5-2) was added thereto, and thereaction mixture was stirred at room temperature for 0.75 hours. Waterwas added to the reaction mixture, and this was subjected to extractionwith ethyl acetate-tetrahydrofuran, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia BW-300, ethylacetate) to yield a pale brown oil. This oil was dissolved intetrahydrofuran (4.0 ml) and methanol (2.0 ml), 4N aqueous solution oflithium hydroxide (0.77 ml) was added at room temperature, and thereaction mixture was stirred at room temperature for 1.5 hours. To thereaction mixture, 1N hydrochloric acid (3.1 ml) was added while stirredat room temperature; and this was subjected to extraction with ethylacetate-tetrahydrofuran, washed with brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. A smallamount of acetone was added to the obtained amorphous solid, and thissolution was diluted with diethyl ether. The crystals were filtered off,washed with diethyl ether, and dried under aeration to yield the titlecompound (200 mg, 0.50 mmol, 66%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.39 (2H, t, J=6.2 Hz), 2.84 (3H, d,J=4.0 Hz), 3.30 (2H, m), 6.51 (1H, d, J=5.8 Hz), 6.68 (1H, d, J=3.2 Hz),6.87 (1H, s), 7.05 (1H, d, J=9.0 Hz), 7.37 (1H, s), 7.88 (1H, d, J=3.2Hz), 8.01 (1H, d, J=5.8 Hz), 8.16 (1H, m), 8.17 (1H, d, J=4.0 Hz), 8.29(1H, d, J=9.0 Hz), 9.10 (1H, s), 12.24 (1H, s).

Example 27N1-Ethyl-5-(2-(((2-ethoxyethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate(100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1.0 ml), and2-ethoxyethylamine (0.063 ml, 0.6 mmol) was added while stirred at roomtemperature. After 1 hour, the reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with water andbrine, and dried over anhydrous sodium sulfate. After the solvent wasdistilled off, the crystals were precipitated from ethyl acetate-hexane(1:5), filtered off, and dried under aeration to yield the titlecompound (100 mg, 0.24 mmol, quantitative) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.09 (3H, t, J=7.2 Hz), 1.17 (3H, t,J=7.2 Hz), 3.21-3.45 (8H, m), 6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d,J=3.6 Hz), 6.87 (1H, brs), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d,J=2.4 Hz), 7.91 (1H, d, J=3.6 Hz), 8.01 (1H, d, J=5.6 Hz), 8.12 (1H, m),8.22 (1H, t, J=4.8 Hz), 8.28 (1H, d, J=8.8 Hz), 9.08 (1H, s).

The starting materials were synthesized by the following methods.

Production Example 27-1N1-Ethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Sodium hydride (573 mg, 14.32 mmol) was suspended inN,N-dimethylformamide (30 ml) under nitrogen atmosphere.4-(1H-5-Indolyloxy)-2-pyridinamine (3.00 g, 13.32 mmol, CAS No.417722-11-3) described in WO 02/32872 was gradually added thereto whilestirred at room temperature. After 10 minutes, the reaction mixture wascooled with an ice water bath, and phenyl N-ethylcarbamate (2.31 g,13.98 mmol) was added. The reaction mixture was heated to roomtemperature and was stirred for 2 hours. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was distilled off, then the crystals were precipitated fromethyl acetate, filtered off, and dried under aeration to yield the titlecompound (3.168 g, 10.69 mmol, 80.3%) as pale brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.32 (3H, t, J=7.2 Hz), 2.40-2.50(2H, m), 5.74 (1H, d, J=2.4 Hz), 5.83 (2H, brs), 6.12 (1H, dd, J=2.4,5.6 Hz), 6.66 (1H, d, J=3.6 Hz). 7.01 (1H, dd, J=2.4, 8.8 Hz), 7.32 (1H,d, J=2.4 Hz), 7.75 (1H, d, J=5.6 Hz), 7.88 (1H, d, J=3.6 Hz), 8.19 (1H,t, J=5.6 Hz), 8.26 (1H, d, J=8.8 Hz).

Production Example 27-2 PhenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate

N1-ethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (3.168 g, 10.69mmol) synthesized in Production example 27-1 was dissolved inN,N-dimethylformamide (30 ml) under nitrogen atmosphere. Pyridine (1.25ml, 15.40 mmol) and phenyl chlorocarbonate (1.61 ml, 12.83 mmol) weresequentially added dropwise while cooled with an ice water bath. Thereaction mixture was heated to room temperature while stirred. After 1hour, the reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was distilled off, and thecrystals were precipitated from ethyl acetate, filtered off, and driedunder aeration to yield the title compound (1.530 g, 3.67 mmol, 34.4%)as white crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.32 (3H, t, J=7.2 Hz), 3.53 (2H, m),5.48 (1H, m), 6.58 (1H, d, J=4.0 Hz), 6.62 (1H, dd, J=2.4, 5.6 Hz), 7.06(1H, dd, J=2.4, 8.8 Hz), 7.15 (2H, m), 7.20-7.27 (1H, m), 7.30 (1H, d,J=2.4 Hz), 7.37 (2H, m), 7.45 (1H, d, J=4.0 Hz), 7.52 (1H, d, J=2.4 Hz),8.10-8.15 (3H, m).

Example 28N1-Methyl-5-(2-((4-(2-hydroxy-2-methylpropionyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-indolecarboxamide

N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53mmol) synthesized in Production example 5-1 was dissolved intetrahydrofuran (3 ml). Triethylamine (0.37 ml, 2.66 mmol) and phenylchlorocarbonate (0.15 ml, 1.2 mmol) were sequentially added dropwise atroom temperature, and the reaction mixture was stirred for 30 minutes.1-(2-Hydroxy-2-methylpropionyl)piperazine (412 mg, 2.39 mmol) andN,N-dimethylformamide (3 ml) were added and the reaction mixture wasstirred for 3 days. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water and brine,and dried over anhydrous sodium sulfate. The solvent was distilled off,and the residue was purified by silica gel column chromatography(eluent; ethyl acetate:methanol=95:5). The crystals were precipitatedfrom diethyl ether-hexane (1:2), filtered off, and dried under aerationto yield the title compound (189.4 mg, 0.39 mmol, 74.2%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.28 (6H, s), 2.83 (3H, d, J=4.0 Hz),3.10-3.50 (8H, m), 5.43 (1H, s), 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H,d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.30 (1H, d, J=2.4 Hz), 7.36(1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.08 (1H, d, J=5.6 Hz), 8.16(1H, q, J=4.0 Hz), 8.28 (1H, d, J=8.8 Hz), 9.21 (1H, s).

1-(2-Hydroxy-2-methylpropionyl)piperazine was synthesized by thefollowing methods.

Production Example 28-1 Benzyl4-(2-hydroxy-2-methylpropionyl)piperazine-1-carboxylate

Benzyl piperazine-1-carbamate (2.203 g, 10.0 mmol) was dissolved intetrahydrofuran (50 ml); 2-hydroxy-2-methylpropionic acid (1.25 g, 12.0mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30g, 12.0 mmol), 1-hydroxy-1H-benzotriazole monohydrate (1.84 g, 12.0mmol) and triethylamine (3.35 ml, 24.0 mmol) were added; and thereaction mixture was stirred at room temperature for 7 hours. Thereaction mixture was partitioned between ethyl acetate and 1Nhydrochloric acid. The organic layer was washed with water, a saturatedaqueous solution of sodium hydrogencarbonate and brine, and dried overanhydrous sodium sulfate. The solvent was distilled off, and dried underreduced pressure to yield the title compound (2.823 g, 9.21 mmol, 92.1%)as a colorless oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50 (6H, s), 3.52-3.55 (4H, m),3.60-3.70 (4H, m), 3.93 (1H, s), 5.16 (2H, s), 7.34-7.38 (5H, m).

Production Example 28-2 1-(2-Hydroxy-2-methylpropionyl)piperazine

Benzyl 4-(2-hydroxy-2-methylpropionyl)piperazine-1-carbamate (2.82 g,9.20 mmol) synthesized in Production example 28-1 was dissolved inmethanol (100 ml) under nitrogen atmosphere; 10% palladium on carbon(50% wet, 1.96 g) was added thereto, the reaction system was purged withhydrogen at atmospheric pressure; and the reaction mixture was stirredovernight. After the reaction system was purged with nitrogen, thecatalyst was filtered out, and washed with methanol, then the solvent,together with the filtrate and the washing solution, was distilled off.The residue was dried under reduced pressure to yield the title compound(1.58 g, 9.20 mmol, quantitative) as a colorless oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.49 (6H, s), 2.84-2.94 (4H, m), 3.49(1H, s), 3.62-3.70 (4H, m).

Example 29N1-Methyl-5-(2-((3-diethylamino)propylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (96.4 mg, 0.22 mmol, 73.3%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (121mg, 0.30 mmol) and 3-(diethylamino)propylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.91 (6H, t, J=7.2 Hz), 1.50 (2H, m),2.30-2.44 (6H, m), 2.83 (3H, d, J=4.4 Hz), 3.23 (2H, m), 6.50 (1H, dd,J=2.4, 6.0 Hz), 6.68 (1H, d, J=3.6 Hz), 6.82 (1H, s), 7.04 (1H, dd,J=2.4, 8.8 Hz), 7.37 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.01(1H, d, J=6.0 Hz), 8.10-8.17 (2H, m), 8.29 (1H, d, J=8.8 Hz), 9.04 (1H,s).

The starting material was synthesized as follows.

Production Example 29-1 PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate

N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (2.163 g, 7.66mmol) synthesized in Production example 5-1 was dissolved inN,N-dimethylformamide (50 ml) under nitrogen atmosphere; pyridine (0.93ml, 11.5 mmol), triethylamine (2.4 ml, 17.24 mmol) and phenylchlorocarbonate (1.44 ml, 11.5 mmol) were sequentially added dropwisewhile cooled with an ice water bath; and the reaction mixture was heatedto room temperature while stirred. After 1 hour, the reaction mixturewas partitioned between ethyl acetate and water. The organic layer waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was distilled off, and then the residue was purified bysilica gel column chromatography (eluent; ethyl acetate), precipitatedfrom ethyl acetate-hexane (1:10), filtered off, and dried under aerationto yield the title compound (2.731 g, 6.79 mmol, 88.6%) as whitecrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.09 (3H, d, J=4.8 Hz), 5.52 (1H, m),6.62 (1H, d, J=3.6 Hz), 6.98 (1H, dd, J=2.4, 5.6 Hz), 7.01 (1H, d, J=2.4Hz), 7.11 (1H, dd, J=2.4, 8.8 Hz), 7.14-7.40 (7H, m), 7.47 (1H, d, J=3.6Hz), 8.24 (1H, d, J=8.8 Hz), 8.41 (1H, d, J=5.6 Hz).

Example 30N1-Methyl-5-(2-(((3-4-hydroxypiperidino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (51.3 mg, 0.11 mmol, 29.5%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (150mg, 0.37 mmol, Production example 29-1) and1-(3-aminopropyl)-4-hydroxypiperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.29-1.38 (2H, m), 1.50-1.55 (2H, m),1.64-1.68 (2H, m), 1.88-1.92 (2H, m), 2.20-2.24 (2H, m), 2.62-2.66 (2H,m), 2.83 (3H, d, J=4.4 Hz), 3.06-3.12 (2H, m), 3.39 (1H, m), 4.49 (1H,d, J=4.0 Hz), 6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.84(1H, s), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, s), 7.87 (1H, d, J=3.6Hz), 8.01 (1H, d, J=5.6 Hz), 8.05 (1H, m), 8.16 (1H, q, J=4.4 Hz), 8.28(1H, d, J=8.8 Hz), 9.02 (1H, s).

Example 31N1-Methyl-5-(2-(((3-(4-methylpiperazin-1-yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (133.2 mg, 0.29 mmol, 76.8%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (150mg, 0.37 mmol, Production example 29-1) and1-(3-aminopropyl)-4-methylpiperazine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.53 (2H, m), 2.11 (3H, s), 2.11-2.40(10H, m), 2.83 (3H, d, J=4.0 Hz), 3.09 (2H, m), 6.50 (1H, dd, J=2.4, 5.6Hz), 6.67 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.03 (1H, dd, J=2.4, 8.8 Hz),7.36 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.01 (1H, d, J=5.6 Hz),8.05 (1H, m), 8.16 (1H, q, J=4.0 Hz), 8.28 (1H, d, J=8.8 Hz), 9.01 (1H,s).

Example 325-(2-(3-(4-Oxo-4-(pyrrolidin-1-yl)butyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

The title compound (113 mg, 0.24 mmol, 77%) was obtained as colorlesscrystals by performing the reaction similar to Example 8 using4-((4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyricacid (130 mg, 0.31 mmol) and pyrrolidine (0.053 ml, 0.63 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.64 (2H, m), 1.71 (2H, m), 1.82 (2H,m), 2.20 (2H, t, J=6.8 Hz), 2.83 (3H, d, J=4.0 Hz), 3.09 (2H, q, J=6.8Hz). 3.22 (2H, t, J=6.8 Hz), 3.33 (2H, m), 6.50 (1H, dd, J=2.4, 5.8 Hz),6.67 (1H, d, J=3.6 Hz), 6.86 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 9.0Hz), 7.36 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.00 (1H, m), 8.03(1H, d, J=5.8 Hz), 8.16 (1H, m), 8.28 (1H, d, J=9.0 Hz), 9.00 (1H, s).

The starting material was synthesized by the following methods.

Production Example 32-14-((4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyricacid

Ethyl 4-aminobutyrate hydrochloride (1.0 g, 6.0 mmol) was suspended inN,N-dimethylformamide (6.7 ml), 5N aqueous solution of sodium hydroxide(1.2 ml, 6.0 mmol) was added and the reaction mixture was stirred atroom temperature. PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(700 mg, 1.3 mmol, Production example 5-2) was added thereto and thereaction mixture was stirred at room temperature for 1.2 hours. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was dried over anhydrous magnesium sulfate, concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (Fuji Silysia BW-300, ethyl acetate) to yield a paleyellow oil. This oil was dissolved in tetrahydrofuran (6.0 ml) andmethanol (3.0 ml); 4N lithium hydroxide (1.1 ml) was added thereto atroom temperature; and the reaction mixture was stirred at roomtemperature for 3.5 hours. Moreover, 1N hydrochloric acid (4.4 ml) andwater (2 ml) were added thereto while stirred at room temperature; andthis was subjected to extraction with ethyl acetate, washed with brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. After the precipitated crystals were suspended in diethylether:hexane=1:1, the crystals were filtered off, washed with diethylether, and dried under aeration to yield the title compound (411 mg, 1.0mmol, 75%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.63 (2H, m), 2.20 (2H, t, J=7.4 Hz),2.83 (3H, d, J=4.0 Hz), 3.10 (2H, m), 6.52 (1H, d, J=5.4 Hz), 6.68 (1H,d, J=3.6 Hz), 6.87 (1H, s), 7.04 (1H, dd, J=2.4, 9.0 Hz), 7.37 (1H, d,J=2.4 Hz), 7.88 (1H, d, J=3.6 Hz), 8.03 (2H, m), 8.17 (1H, d, J=4.0 Hz),8.29 (1H, d, J=9.0 Hz), 9.03 (1H, s), 12.05 (1H, s).

Example 335-(2-(3-(3-(Cyclopropylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

The title compound (166 mg, 0.37 mmol, 76%) was obtained as colorlesscrystals by performing the reaction similar to Example 8 using4-((4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyricacid (200 mg, 0.49 mmol, Production example 32-1) and cyclopropylamine(0.028 ml, 0.58 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.33-0.37 (2H, m), 0.54-0.59 (2H, m),1.62 (2H, m), 2.02 (2H, t, J=7.4 Hz), 2.58 (1H, m), 2.85 (3H, m), 3.08(2H, m), 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.70 (1H, d, J=3.6 Hz), 6.88 (1H,d, J=2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.39 (1H, d, J=2.4 Hz), 7.86(1H, d, J=3.6 Hz), 7.90 (1H, d, J=3.6 Hz), 8.04 (1H, m), 8.05 (1H, d,J=6.0 Hz), 8.19 (1H, d, J=4.2 Hz), 8.31 (1H, d, J=8.8 Hz), 9.04 (1H, s).

Example 345-(2-(3-(4-(4-Hydroxy-4-methylpiperidin-1-yl)-4-oxobutyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

The title compound (195 mg, 0.383 mmol, 78.9%) was obtained as colorlesscrystals by performing the reaction similar to Example 8 using4-((4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyricacid (200 mg, 0.486 mmol, Production example 32-1) and4-hydroxy-4-methylpiperidine monohydrochloride (110 mg, 0.729 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, s), 1.22-1.44 (4H, m), 1.62(2H, m), 2.27 (2H, t, J=7.4 Hz), 2.83 (3H, d, J=4.0 Hz), 2.97 (1H, m),3.08 (2H, m), 3.29 (1H, m), 3.47 (1H, m), 3.89 (1H, m), 4.33 (1H, s),6.50 (1H, d, J=6.0 Hz), 6.67 (1H, d, J=3.6 Hz), 6.87 (1H, s), 7.04 (1H,d, J=9.2 Hz), 7.36 (1H, s), 7.87 (1H, d, J=3.6 Hz), 8.01 (1H, m), 8.02(1H, d, J=6.0 Hz), 8.16 (1H, m), 8.28 (1H, d, J=9.2 Hz), 9.00 (1H, m).

Example 355-(2-(3-(3-(Diethylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

The title compound (94 mg, 0.20 mmol, 64%) was obtained as colorlesscrystals by performing the reaction similar to Example 8 using4-((4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyricacid (130 mg, 0.31 mmol, Production example 32-1) and diethylamine(0.066 ml, 0.63 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.96 (3H, t, J=7.2 Hz), 1.04 (3H, t,J=7.2 Hz), 1.63 (2H, m), 2.25 (2H, t, J=7.2 Hz), 2.83 (3H, d, J=4.4 Hz),3.09 (2H, m), 3.22 (4H, m), 6.51 (1H, dd, J=2.0, 5.6 Hz), 6.67 (1H, d,J=3.4 Hz), 6.86 (1H, d, J=2.0 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36(1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.4 Hz), 8.02 (2H, m), 8.16 (1H, d,J=4.4 Hz), 8.29 (1H, d, J=8.8 Hz), 9.00 (1H, s).

Example 365-(2-(3-(3-(Methylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

The title compound (107 mg, 0.25 mmol, 69%) was obtained as colorlesscrystals by performing the reaction similar to Example 8 using4-((4-(1-methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyricacid (150 mg, 0.36 mmol, Production example 32-1) and methylaminehydrochloride (49 mg, 0.73 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.61 (2H, m), 2.03 (2H, t, J=7.6 Hz),2.51 (3H, d, J=4.4 Hz), 2.83 (3H, d, J=4.0 Hz), 3.06 (2H, q, J=6.4 Hz),6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.86 (1H, d, J=2.4Hz), 7.03 (1H, dd, J=2.4, 9.2 Hz), 7.36 (1H, d, J=2.4 Hz), 7.71 (1H, m),7.87 (1H, d, J=3.6 Hz), 8.03 (2H, m), 8.16 (1H, d, J=4.4 Hz), 8.28 (1H,d, J=9.2 Hz), 9.01 (1H, s).

Example 37N1-Methyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (265 mg, 0.70 mmol, 69%) wasobtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(532 mg, 1.02 mmol) synthesized in Production example 5-2 andpyrrolidine (0.42 ml, 5.0 mmol).

MS Spectrum (ESI): 380 (M+1), 759 (2M+1)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.78-1.84 (4H, m), 2.83 (3H, d, J=4.5Hz), 3.22-3.36 (4H, m), 6.54 (1H, dd, J=2.3, 5.6 Hz), 6.67 (1H, d, J=3.6Hz), 7.03 (1H, dd, J=2.3, 8.7 Hz), 7.35 (1H, d, J=2.3 Hz), 7.41 (1H, d,J=2.3 Hz), 7.87 (1H, d, J=3.6 Hz), 8.04 (1H, d, J=5.6 Hz), 8.16 (1H, m),8.28 (1H, t, J=8.7 Hz), 8.59 (1H, s).

Example 38N1-Methyl-5-(2-(piperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (265 mg, 0.674 mmol, 76%) wasobtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(463 mg, 0.885 mmol) synthesized in Production example 5-2 andpiperidine (0.44 ml, 4.4 mmol).

MS Spectrum (ESI): 394 (M+1), 787 (2M+1)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.37-1.57 (6H, m), 2.83 (3H, d, J=4.4Hz), 3.26-3.45 (4H, m), 6.54 (1H, dd, J=2.4, 5.4 Hz), 6.67 (1H, d, J=3.4Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.30 (1H, d, J=2.4 Hz), 7.36 (1H, d,J=2.4 Hz), 7.87 (1H, d, J=3.4 Hz), 8.05 (1H, d, J=5.4 Hz), 8.16 (1H, m),8.28 (1H, t, J=8.8 Hz), 9.05 (1H, s).

Example 39N1-Methyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (86.7 mg, 0.21 mmol, 21.2%)was obtained as white powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (402mg, 1.0 mmol) synthesized in Production example 29-1 and4-hydroxypiperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.60-1.70 (2H, m), 1.75 (1H, m), 2.83(3H, d, J=4.4 Hz), 2.95-3.01 (2H, m), 3.55-3.65 (2H, m), 3.71-3.76 (2H,m), 4.64 (1H, d, J=4.0 Hz), 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d,J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.32 (1H, d, J=2.4 Hz), 7.36(1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.6 Hz), 8.16(1H, q, J=4.4 Hz), 8.28 (1H, d, J=8.8 Hz), 9.10 (1H, s).

Example 40N1-Methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(440 mg, 0.841 mmol) synthesized in Production example 5-2 was dissolvedin N,N-dimethylformamide (5 ml); triethylamine (0.543 ml, 3.90 mmol) and4-piperidone hydrochloride monohydrate (0.530 g, 3.93 mmol) were addedthereto; and the reaction mixture was stirred for 2 hours. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was concentrated to yield the title compound (0.202 g, 0.496 mmol,59%) as a colorless amorphous solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.32 (4H, t, J=4.9 Hz), 2.82 (3H, d,J=4.3 Hz), 3.68 (4H, t, J=4.9 Hz), 6.55 (1H, dd, J=2.3, 5.6 Hz), 6.67(1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.3, 8.6 Hz), 7.37 (2H, s), 7.87 (1H,d, J=3.6 Hz), 8.09 (1H, d, J=5.6 Hz), 8.17 (1H, s), 8.28 (1H, t, J=8.6Hz), 9.37 (1H, s).

Example 415-(2-(((4-Hydroxy-4-methylpiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indole-1-carboxylicacid methylamide

4-Hydroxy-4-methylpiperidine monohydrochloride (508 mg, 3.83 mmol,Production example 8-3) was dissolved in N,N-dimethylformamide (8 ml);triethylamine (2 ml) was added; and the reaction mixture was stirred atroom temperature. PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(500 mg, 0.957 mmol, Production example 5-2) was added and the reactionmixture was stirred at room temperature for 8 hours. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was dried over anhydrous magnesium sulfate, and concentrated underreduced pressure; and the residue was purified by silica gel columnchromatography (Fuji Silysia BW-300, ethyl acetate, ethylacetate:methanol=20:1 then 10:1). The obtained amorphous solid wascrystallized by adding diethyl ether:acetone=2:1. Thus obtained crystalswere filtered off, washed with diethyl ether, and dried under aerationto yield the title compound (385 mg, 0.909 mmol, 95.0%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, s), 1.33-1.40 (4H, m), 2.83(3H, d, J=4.4 Hz), 3.14 (2H, m), 3.63 (2H, m), 4.27 (1H, s), 6.53 (1H,dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.4 Hz), 7.03 (1H, dd, J=2.4, 8.8Hz), 7.32 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.4Hz), 8.06 (1H, d, J=5.6 Hz), 8.16 (1H, m), 8.28 (1H, d, J=8.8 Hz), 9.04(1H, s).

Example 42N1-Methyl-5-(2-((4-(1-hydroxy-1-methylethyl)piperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (71.1 mg, 0.16 mmol, 29.7%)was obtained as white crystals fromN1-ethyl-5-((2-amino-4-pyridyl)oxy)-1H-1-indolecarboxamide (150 mg, 0.53mmol) synthesized in Production example 5-1 and4-(1-hydroxy-1-methylethyl)piperidine (342 mg, 2.39 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.99 (6H, s), 1.03-1.09 (2H, m), 1.30(1H, m), 1.60-1.64 (2H, m), 2.54-2.61 (2H, m), 2.83 (3H, d, J=4.4 Hz),4.08 (1H, s), 4.10-4.15 (2H, m), 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H,d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.32 (1H, d, J=2.4 Hz), 7.36(1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.6 Hz), 8.16(1H, q, J=4.0 Hz), 8.27 (1H, d, J=8.8 Hz), 9.04 (1H, s).

4-(1-Hydroxy-1-methylethyl)piperidine was synthesized in the followingmethods.

Production Example 42-1 Benzyl 4-ethoxycarbonylpiperidine-1-carboxylate

4-Ethoxycarbonylpiperidine (1.572 g, 10.0 mmol) was dissolved intetrahydrofuran (50 ml); triethylamine (2.79 ml, 20.0 mmol) and benzylchlorocarbonate (1.71 ml, 12.0 mmol) were added dropwise while cooledwith an ice water bath; and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was partitioned betweenethyl acetate and the saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was washed with brine and driedover anhydrous sodium sulfate. The solvent was distilled off, and theresidue was purified by silica gel column chromatography (eluent; ethylacetate:hexane=1:3) to yield the title compound (2.315 g, 7.95 mmol,79.5%) as a colorless oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.26 (3H, t, J=7.2 Hz), 1.60-1.70 (2H,m), 1.80-2.00 (2H, m), 2.46 (1H, m), 2.80-3.00 (2H, m), 4.00-4.20 (2H,m), 4.15 (2H, q, J=7.2 Hz), 5.13 (2H, s), 7.29-7.38 (5H, m).

Production Example 42-2 Benzyl4-(1-hydroxy-1-methylethyl)piperidine-1-carboxylate

Benzyl 4-ethoxycarbonylpiperidine-1-carboxylate (2.315 g, 7.95 mmol)synthesized in Production example 42-1 was dissolved in tetrahydrofuran(25 ml) under nitrogen atmosphere; methyl magnesium bromide (0.93 M) intetrahydrofuran (32.5 ml, 30.2 mmol) was added dropwise while cooledwith an ice water bath; and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was partitioned betweenethyl acetate and the saturated aqueous solution of ammonium chloride.The organic layer was washed with brine and dried over anhydrous sodiumsulfate. The solvent was distilled off, and the residue was purified bysilica gel column chromatography (eluent; ethyl acetate:hexane=1:1) toyield the title compound (1.786 g, 6.44 mmol, 81%) as a colorless oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.18 (6H, s), 1.18-1.27 (2H, m),1.40-1.48 (1H, m), 1.74-1.78 (2H, m), 2.60-2.80 (2H, m), 4.20-4.40 (2H,m), 5.13 (2H, s), 7.27-7.37 (5H, m).

Production Example 42-3 4-(1-Hydroxy-1-methylethyl)piperidine

Benzyl 4-(1-hydroxy-1-methylethyl)piperidine-1-carboxylate (1.786 g,6.44 mmol) synthesized in Production example 42-2 was dissolved inmethanol (100 ml) under nitrogen atmosphere; 10% palladium on carbon(50% wet, 1.37 g) was added; the reaction system was purged withhydrogen at atmospheric pressure; and the reaction mixture was stirredovernight. After the reaction system was purged with nitrogen, thecatalyst was filtered out, and washed with methanol; the solvent,together with the filtrate and the washing solution, was distilled off;and the residue was dried under reduced pressure to yield the titlecompound (922 mg, 6.44 mmol, quantitative) as pale gray crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.18 (6H, s), 1.26-1.42 (3H, m),1.74-1.80 (2H, m), 2.57-2.64 (2H, m), 3.14-3.22 (2H, m), 3.48 (1H, s).

Example 435-(2-(((4-(3-Methylcarbamoylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

4-(1-((4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonyl)piperidin-4-yl)butyricacid (170 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (7.0ml); methylamine hydrochloride (48 mg, 0.71 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(314 mg, 0.71 mmol) and triethylamine (0.35 ml) were added thereto; andthe reaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia NH silicagel, hexane-ethyl acetate-methanol system). After a small amount ofacetone and ethyl acetate were added to the obtained amorphous solid;this solution was diluted with diethyl ether; and the solid portion wasfiltered off, washed with diethyl ether, and dried under aeration toyield the title compound (30 mg, 0.061 mmol, 17%) as a colorlessamorphous solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.87-1.00 (2H, m), 1.13 (2H, m), 1.33(1H, m), 1.46 (2H, m), 1.57 (2H, m), 1.99 (2H, t, J=7.4 Hz), 2.52 (3H,d, J=4.4 Hz), 2.65 (2H, m), 2.83 (3H, d, J=4.0 Hz), 4.03 (2H, m), 6.53(1H, d, J=6.0 Hz), 6.67 (1H, d, J=3.4 Hz), 7.03 (1H, d, J=9.0 Hz), 7.31(1H, s), 7.35 (1H, s), 7.66 (1H, m), 7.87 (1H, d, J=3.4 Hz), 8.06 (1H,d, J=4.0 Hz), 8.16 (1H, d, J=4.0 Hz), 8.27 (1H, d, J=9.0 Hz), 9.05 (1H,s).

The starting materials were synthesized as follows.

Production Example 43-1 tert-Butyl4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate

tert-Butyl 4-(2-(toluene-4-sulfonyloxy)ethyl)piperidine-1-carboxylate(7.55 g, 19.7 mmol, CAS No. 89151-45-1) as described in WO 02/32872 wasdissolved in ethanol; diethyl malonate (3.3 ml, 21.3 mmol) and sodiumethoxide (1.45 g, 21.3 mmol) were added; and the reaction mixture washeated to reflux under nitrogen atmosphere for 2.5 hours. Afternaturally cooled to room temperature, the saturated aqueous solution ofammonium chloride was added; this was subjected to extraction with ethylacetate, washed with brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. After the residue was dissolved indimethyl sulfoxide (20 ml); lithium chloride (1.7 g, 40 mmol) and water(0.36 ml, 20 mmol) were added; and the reaction mixture was stirred at185° C. for 1.5 hours and further stirred at 195° C. for 2 hours. Afternaturally cooled to room temperature, the reaction mixture waspartitioned between ethyl acetate-brine. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (Fuji Silysia BW-300, hexane-ethyl acetate system) toyield the title compound (2.60 g, 8.7 mmol, 43%) as a pale yellow oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.02-1.13 (2H, m), 1.23-1.29 (5H, m),1.39 (1H, m), 1.45 (9H, s), 1.62-1.69 (4H, m), 2.29 (2H, t, J=7.4 Hz),2.67 (2H, m), 4.07 (2H, m), 4.13 (2H, q, J=7.2 Hz).

Production Example 43-2 Ethyl 4-(piperidin-4-yl)butyrate

tert-Butyl 4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate (1.2 g,4.0 mmol, Production example 43-1) was dissolved in trifluoroacetic acid(30 ml), and the reaction mixture was stirred at room temperature for 20minutes. This was concentrated under reduced pressure, and was furtherazeotropically distilled with toluene. The obtained residue waspartitioned between ethyl acetate and a saturated aqueous solution ofsodium hydrogencarbonate. The organic layer was dried over anhydrousmagnesium sulfate. In addition, the aqueous layer was concentrated underreduced pressure to dryness; the obtained solid was suspended intetrahydrofuran; insoluble portion were filtered off, and this solutionwas added to the previously obtained organic layer. This was purified bysilica gel column chromatography (Fuji Silysia NH, hexane-ethylacetate-methanol system) to yield the title compound (1.15 g,quantitative) as a yellow oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.26 (3H, m), 1.28-1.37 (2H, m),1.40-1.52 (3H, m), 1.64 (2H, m), 1.86 (2H, m), 2.29 (2H, t, J=7.4 Hz),2.82 (2H, m), 3.35 (2H, m), 4.13 (2H, m).

Production Example 43-35-(2-(((4-(3-Ethoxycarbonylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Ethyl 4-(piperidin-4-yl)butyrate (650 mg, 2.0 mmol, Production example43-2) was suspended in N,N-dimethylformamide (3.35 ml); phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(350 mg, 0.67 mmol, Production example 5-2) was added; and the reactionmixture was stirred at room temperature for 1 hour. The reaction mixturewas partitioned between ethyl acetate and water. The organic layer wasdried over anhydrous magnesium sulfate, concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Fuji Silysia BW-300, hexane-ethyl acetate-methanol system) to yield thetitle compound (271 mg, 0.54 mmol, 80%) as a pale yellow oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.05-1.16 (2H, m), 1.22-1.28 (5H, m),1.43 (1H, m), 1.62 (2H, m), 1.71 (2H, m), 2.27 (2H, t, J=7.4 Hz), 2.80(2H, m), 2.95 (3H, d, J=4.4 Hz), 3.99 (2H, m), 4.12 (2H, q, J=7.2 Hz),6.09 (1H, d, J=4.4 HZ), 6.46 (1H, d, J=3.4 Hz), 6.58 (1H, dd, J=2.0, 5.6Hz), 7.04 (1H, dd, J=2.0, 8.8 Hz), 7.24 (1H, s), 7.28 (1H, d, J=2.0 Hz),7.32 (1H, d, J=3.4 Hz), 7.54 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=5.6 Hz),8.20 (1H, d, J=8.8 Hz).

Production Example 43-44-(1-((4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonyl)piperidin-4-yl)butyricacid

5-(2-((4-(3-Ethoxycarbonylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide (271 mg, 0.54 mmol, Production example 43-3) wasdissolved in tetrahydrofuran (3.0 ml) and methanol (1.5 ml); 4N lithiumhydroxide (0.54 ml) was added; and the reaction mixture was stirred atroom temperature for 3.5 hours. 1N hydrochloric acid (2.2 ml) was addedthereto while the stirred at room temperature. After the precipitatedcrystals were filtered off, the crystals were washed with water anddiethyl ether sequentially, and dried under aeration to yield the titlecompound (170 mg, 0.35 mmol, 66%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (2H, m), 1.16 (2H, m), 1.36 (1H,m), 1.47 (2H, m), 1.58 (2H, m), 2.15 (2H, t, J=7.4 Hz), 2.66 (2H, m),2.83 (3H, d, J=4.2 Hz), 4.02 (2H, m), 6.53 (1H, d, J=6.0 Hz), 6.67 (1H,d, J=3.4 Hz), 7.03 (1H, d, J=9.2 Hz), 7.31 (1H, s), 7.35 (1H, s), 7.86(1H, d, J=3.4 Hz), 8.05 (1H, d, J=6.0 Hz), 8.15 (1H, d, J=4.2 Hz), 8.27(1H, d, J=9.2 Hz), 9.02 (1H, s).

Example 445-(2-(((4-(3-Carbamoylpropyl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

4-(Piperidin-4-yl)butanamide (547 mg, 1.41 mmol) was dissolved inN,N-dimethylformamide (3 ml); phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(210 mg, 0.402 mmol, the product of Production example 5-2) was addedthereto; and the reaction mixture was stirred at room temperature for1.5 hour. The reaction mixture was partitioned between ethyl acetate andwater; the organic layer was dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure; and the residue was purified bysilica gel column chromatography (Fuji Silysia NH, ethylacetate-methanol system). The obtained amorphous solid was crystallizedby adding diethyl ether. After addition of a small amount of ethanol tomake a suspension, this was diluted with hexane. After separation byfiltration to obtain crystals, these were rinsed with diethyl ether anddried under aeration. Thus, the title compound was obtained as colorlesscrystals (157 mg, 0.328 mmol, 81.7%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.87-1.00 (2H, m), 1.10-1.16 (2H, m),1.35 (1H, m), 1.42-1.50 (2H, m), 1.58 (2H, m), 1.98 (2H, t, J=7.4 Hz),2.65 (2H, m), 2.83 (3H, d, J=4.0 Hz), 4.03 (2H, m), 6.53 (1H, dd, J=2.0,5.6 Hz), 6.67 (2H, m), 7.03 (1H, dd, J=2.0, 9.0 Hz), 7.20 (1H, s), 7.31(1H, d, J=2.0 Hz), 7.35 (1H, d, J=2.0 Hz), 7.87 (1H, d, J=3.2 Hz), 8.06(1H, d, J=5.6 Hz), 8.16(1H, m), 8.28 (1H, d, J=9.0 Hz), 9.05 (1H, s).

The starting materials were synthesized as follows.

Production Example 44-1 tert-Butyl4-(3-carbamoylpropyl)piperidine-1-carboxylate

tert-Butyl 4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate (0.60 g,2.0 mmol, the product of Production example 43-1) and formamide (0.27ml, 6.7 mmol) were dissolved in N,N-dimethylformamide (1.0 ml); sodiumethoxide (0.095 g, 1.4 mmol) was added thereto while stirred and heatedat 100° C.; the reaction mixture was stirred for 2 hours under nitrogenatmosphere. After cooled to room temperature, the reaction mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel chromatography (eluent; hexane-ethyl acetate=95:5to 85:15). The title compound was obtained as a colorless oil (0.38 g,1.4 mmol, 70%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.03-1.14 (2H, m), 1.26-1.31(2H, m),1.35-1.45 (1H, m), 1.46 (9H, s), 1.63-1.71 (4H, m), 2.22 (2H, t, J=7.6Hz), 2.67 (2H, m), 4.07 (2H, brs), 5.30 (1H, brs), 5.39 (1H, brs).

Production Example 44-2 4-(Piperidin-4-yl)butanamide

tert-Butyl 4-(3-carbamoylpropyl)piperidine-1-carboxylate (0.38 g, 1.4mmol, Production example 44-1) was dissolved in trifluoroacetic acid (2ml) and the reaction mixture was stirred at room temperature for 20minutes. The reaction mixture was concentrated under reduced pressureand then azeotropically distilled with toluene. The residue waspartitioned between tetrahydrofuran and a saturated aqueous solution ofsodium hydrogencarbonate; and the organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure; and theresidue was purified by silica gel chromatography (Fuji Silysia NH,ethyl acetate-methanol system) to yield the title compound (0.55 g,quantitative) as pale yellow oil.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.90-1.01 (2H, m), 1.09-1.15 (2H, m),1.26 (1H, m), 1.45 (2H, m), 1.55 (2H, m), 1.98 (2H, t, J=7.4 Hz), 2 43(2H, m), 2.91 (2H, m), 6.65 (1H, s), 7.20 (1H, s).

Example 455-(2-((4-Pyrrolidin-1-yl)carbonyl)piperidin-1-yl)carbonylamino)pyridin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (134 mg, 0.273 mmol, 91%) wasobtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(157 mg, 0.300 mmol) synthesized in Production example 5-2 and(piperidin-4-yl)-(pyrrolidin-1-yl)methanone (328 mg, 1.50 mmol) obtainedfrom N-benzyloxycarbonylisonipecotic acid and pyrrolidine by the methodsimilar to Example 21.

¹H NMR Spectrum (DMSO-d₆) δ (ppm): 1.35-1.48 (2H, m), 1.56-1.65 (2H, m),1.71-1.80 (2H, m), 1.82-1.91 (2H, m), 2.61 (1H, m), 2.73-2.84 (2H, m),2.85 (3H, d, J=4.4 Hz), 3.22-3.28 (2H, m), 3.44-3.50 (2H, m), 4.04-4.12(2H, m), 6.56 (1H, d, J=6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 7.06 (1H, dd,J=2.4, 9.2 Hz), 7.34 (1H, s), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6Hz), 8.09 (1H, d, J=6.0 Hz) 8.18 (1H, q, J=4.4 Hz), 8.30 (1H, d, J=9.2Hz), 9.16 (1H, s).

Example 46N1-Methyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (88.5 mg, 0.19 mmol, 63.8%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (121mg, 0.30 mmol, Production example 29-1) and4-(1-pyrrolidinyl)piperidine.

PhenylN1-methyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamidemay be synthesized by the following methods.

PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(12.1 g, 23.2 mmol) synthesized in Production example 5-2 was dissolvedin dimethylformamide (150 ml); 4-(1-pyrrolidinyl)piperidine (14.4 g,93.3 mmol) was added thereto; and the reaction mixture was stirred atroom temperature for 16 hours. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with brineand concentrated to about 100 ml. The residue was allowed to be keptcool at 5° C. for overnight to precipitate crystals. The crystals werefiltered off, washed with ethyl acetate to yield the title compound (7.8g, 16.9 mmol, 73%) as white crystals.

¹H NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.33 (2H, m), 1.60-1.70 (4H, m),1.70-1.80 (2H, m), 2.40-2.60 (5H, m), 2.77-2.84 (5H, m), 3.90-4.00 (2H,m), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz) 7.03 (1H, dd,J=2.4, 8.8 Hz), 7.31 (1H, s), 7.35 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6Hz), 8.06 (1H, d. J=5.6 Hz), 8.16 (1H, m), 8.28 (1H, d, J=8.8 Hz), 9.11(1H, s).

Example 47N1-Methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (94.6 mg, 0.20 mmol, 66.2%)as white crystals was obtained from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (121mg, 0.30 mmol, Production example 29-1) and 4-piperidinopiperidine.

N1-Methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamidemay be prepared by the following methods.

PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(15.5 g, 29.7 mmol) synthesized in Production example 5-2 was dissolvedin dimethylformamide (180 ml); 4-piperidinopiperidine (20.0 g, 119 mmol)was added thereto; and the reaction mixture was stirred at roomtemperature for 9 hours. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with brine andconcentrated to about 100 ml. The residue was allowed to be kept cool at5° C. overnight to precipitate crystals. The crystals were filtered offand washed with ethyl acetate to yield the title compound (4.0 g, 8.4mmol, 28%) as white crystals.

¹H NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.65 (10H, m), 2.31-2.40 (5H,m), 2.66 (2H, m), 2.83 (3H, d, J=4.4 Hz), 4.08 (2H, m), 6.53 (1H, dd,J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz),7.31 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz),8.06 (1H, d, J=5.6 Hz), 8.16 (1H, q, J=4.4 Hz), 8.28 (1H, d, J=8.8 Hz),9.09 (1H, s).

Example 48N1-Methyl-5-(2-((4-ethylpiperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (73.2 mg, 0.17 mmol, 57.8%)was obtained as white powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (121mg, 0.30 mmol, Production example 29-1) and 1-ethylpiperazine.

¹H NMR Spectrum (DMSO-d₆) δ (ppm): 0.97 (3H, t, J=7.2 Hz), 2.25-2.32(6H, m), 2.83 (3H, d, J=4.0 Hz), 3.20-3.40 (4H, m), 6.55 (1H, dd, J=2.4,5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.31 (1H,d, J=2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.07 (1H,d, J=5.6 Hz), 8.16 (1H, q, J=4.0 Hz), 8.28 (1H, d, J=8.8 Hz), 9.13 (1H,s).

Example 49N1-Methyl-5-(2-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (97.6 mg, 0.22 mmol, 59.7%)was obtained as pale pink powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (150mg, 0.37 mmol, Production example 29-1) and1-(2-hydroxyethyl)piperazine.

¹H NMR Spectrum (DMSO-d₆) δ (ppm): 2.30-2.40 (6H, m), 2.83 (3H, d, J=4.0Hz), 3.20-3.40 (4H, m), 3.46 (2H, m), 4.39 (1H, t, J=5.6 Hz), 6.55 (1H,dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8Hz), 7.31 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6Hz), 8.06 (1H, d, J=5.6 Hz), 8.16 (1H, q, J=4.0 Hz), 8.27 (1H, d, J=8.8Hz), 9.12 (1H, s).

Example 50N1-Methyl-5-(2-((3-methylsulfonylpropylamino)carbonyl)amino-4-pyridyl)-oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (166.8 mg, 0.37 mmol, 70.5%)was obtained as white crystals fromN1-methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53mmol, Production example 5-1) and 3-methylsulfonylpropylaminehydrochloride (410 mg, 2.36 mmol).

¹H NMR Spectrum (DMSO-d₆) δ (ppm): 1.70-1.90 (2H, m), 2.83 (3H, d, J=4.4Hz), 2.94 (3H, s), 3.04-3.09 (2H, m), 3.17-3.24 (2H, m), 6.52 (1H, dd,J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.86 (1H, s), 7.03 (1H, dd,J=2.4, 8.8 Hz), 7.36 (1H, s), 7.87 (1H, d, J=3.6 Hz), 8.03 (1H, d, J=5.6Hz), 8.10-8.17 (2H, m), 8.28 (1H, d, J=8.8 Hz), 9.07 (1H, s).

Example 51N1-Methyl-5-(2-((4-(2-dimethylaminoacetyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (189.8 mg, 0.40 mmol, 74.5%)was obtained as white powder fromN1-methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53mmol, Production example 5-1) and 1-(2-dimethylaminoacetyl)piperazine(500 mg, 2.92 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.14 (6H, s), 3.04 (3H, d, J=4.0 Hz),3.29 (2H, s), 3.20-3.49 (8H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H,d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz) 7.30 (1H, d, J=2.4 Hz), 7.36(1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.08 (1H, d, J=5.6 Hz), 8.16(1H, q, J=4.0 Hz), 8.28 (1H, d, J=8.8 Hz), 9.24 (1H, s).

1-(2-Dimethylaminoacetyl)piperazine was prepared by the followingmethods.

Production Example 51-1 Benzyl4-(2-dimethyaminoacetyl)piperazine-1-carboxylate

Benzyl piperazine-1-carbamate (2.203 g, 10.0 mmol) was dissolved intetrahydrofuran (50 ml); 2-dimethylaminoacetic acid (1.24 g, 12.0 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g,12.0 mmol), 1-hydroxy-1H-benzotriazole monohydrate (1.84 g, 12.0 mmol)and triethylamine (3.35 ml, 24.0 mmol) were added thereto; and thereaction mixture was stirred at room temperature for 7 hours. Thereaction mixture was partitioned between ethyl acetate and a saturatedaqueous solution of sodium hydrogencarbonate. The organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate,water and brine, dried over anhydrous sodium sulfate, and the residuewas purified by NH silica gel column chromatography (eluent; ethylacetate:hexane=3:1) to yield the title compound (954 mg, 3.12 mmol,31.2%) as a colorless oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.26 (6H, s), 3.11 (2H, s), 3.45-3.65(8H, m), 5.15 (2H, s), 7.32-7.38 (5H, m).

Production Example 51-2 1-(2-Dimethylaminoacetyl)piperazine

Benzyl 4-(2-dimethyaminoacetyl)piperazine-1-carbamate (954 mg, 3.12mmol) synthesized in Production example 51-1 was dissolved in methanol(50 ml) under nitrogen atmosphere; 10% palladium on carbon (50% wet, 665mg) was added thereto; the reaction system was purged with hydrogen atatmospheric pressure; and the reaction mixture was stirred overnight.After the reaction system was purged with nitrogen, the catalyst wasfiltered out, and washed with methanol. The solvent, together with thefiltrate and washing solution, was distilled off, and the residue wasdried under reduced pressure to yield the title compound (508 mg, 2.97mmol, 95.0%) as a colorless oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.28 (6H, s), 2.80-2.88 (4H, m), 3.11(2H, s), 3.52-3.62 (4H, m).

Example 52N1-Methyl-5-(2-((4-cyclohexylpiperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (121.3 mg, 0.25 mmol, 68.2%)was obtained as white crystals from phenylN-(4-(1-methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (150mg, 0.37 mmol, Production example 29-1) and 1-cyclohexylpiperazine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.00-1.20 (6H, m), 1.53 (2H, m),1.60-1.80 (4H, m), 2.19 (2H, m), 2.30-2.45 (5H, m), 2.83 (3H, d, J=4.0Hz), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd,J=2.4, 8.8 Hz), 7.31 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.87(1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.6 Hz), 8.16 (1H, q, J=4.0 Hz), 8.27(1H, d, J=8.8 Hz), 9.09 (1H, s).

Example 53N4-(4-(1-(Methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide

Similarly to Example 27, the title compound (58.6 mg, 0.15 mmol, 49.4%)was obtained as white powder from phenylN-(4-((1-((methylamino)carbonyl)-1H-5-indolyl)oxy-2-pyridyl)carbamate(121 mg, 0.30 mmol, Production example 29-1) and morpholine.

N4-(4-(1-(Methylamino)carbonyl-1H-5-indolyl)-oxy-2-pyridyl)-4-morpholinecarboxamidemay be prepared by the following methods.

PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(20 g, 38 mmol) synthesized in Production example 5-2 was dissolved inN,N-dimethylformamide (190 ml); morpholine (13.3 mg, 153 mmol) was addedthereto; and the reaction system was stirred at room temperature for 9hours. The reaction mixture was partitioned between ethyl acetate andwater; and the organic layer was washed with brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The obtainedresidue was dissolved in ethyl acetate and a small amount oftetrahydrofuran; this suspension was filtrated with silica gel; andethyl acetate and three different ratio of solvent mixtures of ethylacetate:methanol=20:1, 10:1, and 5:1 were eluted through the gel. Thefiltrate was concentrated under reduced pressure. The residue wasdissolved in diethyl ether (40 ml); hexane (200 ml) was added thereto;and precipitated insoluble syrupy portion was removed from the solution;and the resultant solution was concentrated again under reducedpressure. The residue was dissolved in ethyl acetate (300 ml) and wasallowed to stand at room temperature. After the crystals wereprecipitated, the crystals were filtered off, washed with ethyl acetate,and dried to yield the crude crystals of the title compound (10.3 g). 9g of this crude crystals was suspended in a mixture of tetrahydrofuran(3 ml) and N,N-dimethylformamide (3 ml each); this suspension wasdiluted with ethanol (60 ml); and the crystals were filtered off, washedwith ethanol and dried to yield the title compound as colorless crystals(7.70 g, 19 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.83 (3H, d, J=4.4 Hz), 3.34-3.38(4H, m), 3.50-3.53 (4H, m), 6.56 (1H, dd. J=2.4, 5.6 Hz), 6.67 (1H, d,J=3.6 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.31 (1H, d, J=2.4 Hz), 7.36(1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.08 (1H, d, J=5.6 Hz), 8.17(1H, q, J=4.4 Hz), 8.28 (1H, d, J=8.8 Hz), 9.19 (1H, s).

Example 54N1-Methyl-5-(2-((1,1-dioxothiomorpholin-4-ylcarbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

PhenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(150 mg, 0.278 mmol, Production example 5-2) was dissolved inN,N-dimethylformamide (1.5 ml); 5N aqueous solution of sodium hydroxide(0.29 ml) and 1,1-dioxothiomorpholine hydrochloride (246 mg, 1.44 mmol)were added thereto; and the reaction mixture was stirred at roomtemperature for 5 hours. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (Fuji Silysia BW-300,ethyl acetate). Diethyl ether was added to this to allow to crystallize;and the crystals were filtered off, washed with diethyl ether, and driedunder aeration to yield the title compound as colorless crystals (100mg, 0.226 mmol, 78.5%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.83 (3H, d, J=3.6 Hz), 3.10 (4H, m),3.81 (4H, m), 6.57 (1H, dd, J=1.2, 5.6 Hz), 6.67 (1H, d, J=3.2 Hz), 7.03(1H, dd, J=2.0, 9.2 Hz), 7.32 (1H, m), 7.36 (1H, d, J=2.0 Hz), 7.87 (1H,d, J=3.2 Hz), 8.09 (1H, d, J=5.6 Hz), 8.16 (1H, d, J=3.6 Hz), 8.28 (1H,d, J=9.2 Hz), 9.54 (1H, s).

The starting material was synthesized by the following methods.

Production Examples 54-1 tert-Butyl thiomorpholine-4-carboxylate

Thiomorpholine (5.0 ml, 53 mmol) was dissolved in tetrahydrofuran (200ml); triethylamine (8.1 ml, 58 mmol) was added thereto; and the reactionmixture was stirred at room temperature. tert-Butoxycarbonyl dicarbonate(13.3 ml, 58 mmol) was added thereto and the reaction mixture wasstirred at room temperature for 10 hours. The reaction mixture wasconcentrated under reduced pressure; and the residue was purified bysilica gel column (eluent; hexane:ethyl acetate=from 80:20, 75:25 to70:30) to yield the title compound as colorless crystals (10.4 g, 51mmol).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.46 (9H, s), 2.57 (4H, m), 3.69 (4H,m).

Production Example 54-2 tert-Butyl 1,1-dioxothiomorpholine-4-carboxylate

tert-Butyl thiomorpholine-4-carboxylate (1.91 g, 9.42 mmol) wasdissolved in dichloromethane (50 ml); m-chloroperbenzoic acid (5.0 g, 19mmol) was gradually added while cooled with ice bath, stirred, and undernitrogen atmosphere; and the reaction mixture was stirred at roomtemperature for 12 hours. After addition of a saturated aqueous solutionof sodium thiosulfate, the reaction mixture was kept stirred for awhile; and this was subjected to extraction with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. Triethylamine (8.1 ml, 58 mmol) were added to theobtained crystals; and the reaction mixture was stirred at roomtemperature. tert-Butoxycarbonyl dicarbonate (13.3 ml, 58 mmol) wasadded thereto; and the reaction mixture was stirred at room temperaturefor 10 hours. The reaction mixture was concentrated under reducedpressure; and the obtained crystals were suspended with a solventmixture of diethyl ether:ethanol=10:1, filtered off, washed with diethylether and dried under aeration to yield the title compound as colorlesscrystals (2.03 g, 8.63 mmol, 91.6%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.40 (9H, s), 3.09 (4H, t, J=5.2 Hz),3.72 (4H, t, J=5.2 Hz).

Production Example 54-3 Thiomorpholine 1,1-dioxide monohydrochloride

tert-Butyl 1,1-dioxothiomorpholine-4-carboxylate (2.03 g, 8.63 mmol) wasdissolved in a mixture of hydrochloric acid-methanol 10 (20 ml,purchased from Tokyo Kasei Kogyo Co., Ltd) and tetrahydrofuran (20 ml);hydrochloric acid (4.0 ml) was added thereto during stirring at roomtemperature; and the reaction mixture was stirred at room temperaturefor 3 hours. The reaction mixture was concentrated; methanol (20 ml),tetrahydrofuran (20 ml) and hydrochloric acid (4.0 ml) were added to theobtained crystals. Furthermore, water (10 ml) was added to this solutionto perfectly dissolve the crystals; and this solution was stirred atroom temperature for 1 hour. The solvent was concentrated under reducedpressure; and the obtained crystals were suspended in methanol, filteredoff, washed with methanol, and dried under aeration to yield the titlecompound as colorless crystals (1.49 g, 8.65 mmol, quantitative).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.54 (8H, m), 9.83 (2H, brs).

Example 555-(2-(3-((1R)-1-Hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid ethylamide

Similarly to Example 5, the title compound (118 mg, 0.246 mmol, 82%) wasobtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate(161 mg, 0.300 mmol), and(2R)-2-amino-3-hydroxy-1-(pyrrolidin-1-yl)propan-1-one (265 mg, 1.67mmol) obtained by the method similar to Example 21 from(2R)-2-benzyloxycarbonylamino-3-hydroxypropionic acid and pyrrolidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.19 (3H, t, J=7.2 Hz), 1.70-1.90(4H, m), 3.20-3.60 (8H, m), 4.54 (1H, m), 4.98 (1H, brs), 6.55 (1H, d,J=6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.97 (1H, s), 7.05 (1H, dd, J=2.4,8.8 Hz), 7.39 (1H, d, J=2.4 Hz), 7.92 (1H, d, J=3.6 Hz), 8.05 (1H, d,J=6.0 Hz), 8.08-8.28 (2H, m), 8.30 (1H, d, J=8.8 Hz), 9.21 (1H, s).

The starting material was synthesized as follows.

Production Example 55-1 PhenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate

The reaction similar to Production example 5-2 was performed by usingN1-ethyl-5-(2-aminopyridin-4-yloxy)-1H-indolecarboxamide (2.9 g, 9.9mmol, Production example 27-1), tetrahydrofuran, triethylamine andphenyl chloroformate; the extraction and washing was performed; theobtained residue was crystallized by addition of a solvent mixture ofdiethyl ether:hexane=1:1; and the obtained crystals were filtered off,washed with diethyl ether, and dried under aeration to yield the titlecompound as pale pink crystals (3.7 g, 6.9 mmol, 70%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.2 Hz), 3.29 (2H, m),6.66 (1H, d, J=3.4 Hz), 6.96 (1H, dd, J=2.0, 5.8 Hz), 7.09 (1H, dd,J=2.0, 8.0 Hz), 7.17 (4H, d, J=8.0 Hz), 7.29 (2H, d, J=8.0 Hz),7.41-7.44 (5H, m), 7.51 (1H, d. J=2.0 Hz), 7.92 (1H, d, J=3.4 Hz), 8.22(1H, m), 8.31 (1H, d, J=8.8 Hz), 8.42 (1H, d, J=5.8 Hz).

Example 565-(2-(3-((1S)-1-Hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid ethylamide

Similarly to Example 5, the title compound (132 mg, 0.275 mmol, 92%) wasobtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(161 mg, 0.300 mmol) synthesized in Production example 55-1 and(2S)-2-amino-3-hydroxy-1-(pyrrolidin-1-yl)propan-1-one hydrochloride(synthesized as an intermediate in Example 18).

Example 575-(2-(3-((1R)-1-Hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid ethylamide

Similarly to Example 5, the title compound (127 mg, 0.257 mmol, 86%) wasobtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(161 mg, 0.300 mmol) and(2R)-2-amino-3-hydroxy-1-(piperidin-1-yl)propan-1-one (228 mg, 1.32mmol, synthesized as an intermediate in Example 21).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.19 (3H, t, J=7.2 Hz), 1.38-1.61(6H, m), 3.25-3.53 (8H, m), 4.75 (1H, m), 4.92 (1H, brs), 6.54 (1H, dd,J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.97 (1H, d, J=2.4 Hz), 7.05(1H, dd, J=2.4, 9.0 Hz), 7.38 (1H, d, J=2.4 Hz), 7.92 (1H, d, J=3.6 Hz),8.05 (1H, d, J=6.0 Hz), 8.08-8.27 (2H, m), 8.30 (1H, d, J=9.0 Hz), 9.21(1H, s).

Example 585-(2-(3-((1S)-1-Hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid ethylamide

Similarly to Example 5, the title compound (54.4 mg, 0.110 mmol, 73%)was obtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(80.1 mg, 0.150 mmol) synthesized in Production example 55-1 and(2S)-2-amino-3-hydroxy-1-(piperidin-1-yl)propan-1-one hydrochloride (156mg, 0.748 mmol, synthesized as an intermediate in Example 20).

Example 595-(2-(3-(2-(4-Hydroxy-4-methylpiperidin-1-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid ethylamide

The reaction similar to Example 5 was performed by using((4-(1-ethylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)aceticacid (149 mg, 0.37 mmol) and 4-hydroxy-4-methylpiperidinemonohydrochloride (68 mg, 0.45 mmol, Production example 8-3);purification was performed by silica gel column chromatography (FujiSilysia BW-300, eluent, ethyl acetate:methanol=9:1; Fuji Silysia NH,eluent, ethyl acetate:methanol=10:1; and again Fuji Silysia BW-300,eluent, ethyl acetate-methanol system); and the obtained crystals weresuspended in diethyl ether and filtered off, washed with diethyl etherand dried under aeration to yield the title compound as colorlesscrystals (40 mg, 0.081 mmol, 22%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.10 (3H, s), 1.16 (3H, t, J=7.2 Hz),1.43 (4H, m), 3.01 (2H, m), 3.36 (2H, m), 3.89 (2H, m), 3.96 (2H, d,J=4.4 Hz), 4.37 (1H, s), 6.52 (1H, d, J=5.6 Hz), 6.67 (1H, d, J=3.6 Hz),6.91 (1H, s), 7.03 (1H, d, J=9.0 Hz), 7.37 (1H, s), 7.90 (1H, d, J=3.6Hz), 8.03 (1H, d, J=5.6 Hz), 8.17 (1H, m), 8.22 (1H, m), 8.28 (1H, d,J=9.0 Hz), 9.27 (1H, s).

The starting material was synthesized as follows.

Production Example 59-1((4-(1-Ethylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)aceticacid

Methyl aminoacetate hydrochloride (292 mg, 2.33 mmol) was suspended in asolvent mixture of N,N-dimethylformamide (4 ml) and triethylamine (1ml); phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(250 mg, 0.466 mmol, Production example 55-1) was added thereto; and thereaction mixture was stirred at room temperature for 2 days. Thereaction mixture was partitioned between ethyl acetate and water; andthe organic layer was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The obtained residuewas dissolved in a solvent mixture of tetrahydrofuran (2 ml) andmethanol (1 ml); and 4N aqueous solution of sodium hydroxide was addedthereto while stirred at room temperature; and the reaction mixture wasstirred for 1.5 hour at room temperature. After 1N hydrochloric acid wasadded, extraction was performed with ethyl acetate-tetrahydrofuran,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained crystals were suspended in diethylether, filtered off, washed with dimethyl ether, and dried underaeration to yield the title compound as colorless crystals (149 mg,0.375 mmol, 80.5%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.0 Hz), 3.36 (2H, d,J=7.0 Hz), 3.81(2H, d, J=5.2 Hz), 6.54 (1H, d, J=5.6 Hz), 6.67 (1H, d,J=3.4 Hz), 6.85 (1H, s), 7.04 (1H, dd, J=2.0, 8.8 Hz), 7.37 (1H, d,J=2.0 Hz), 7.90 (1H, d, J=3.4 Hz), 8.05 (1H, d, J=5.6 Hz), 8.20-8.30(3H, m), 9.27 (1H, s), 12.55 (1H, s).

Example 60N1-Ethyl-5-(2-((((1-methyl-4-piperidyl)methyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, a crude product of tert-butyl4-(((((4-((1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)amino)carbonyl)amino)methyl)piperidin-1-carboxylatewas obtained from phenylN-(4-(1-(ethylamino)carbonyl)-1H-5-indolyl)oxy)-2-pyridyl)carbamate (150mg, 0.36 mmol, Production example 27-2) and tert-butyl4-aminomethyl-1-piperidine carboxylate. Trifluoroacetic acid was addedto this at room temperature; the solution was stirred for 30 minutes;trifluoroacetic acid was distilled off; triethylamine-methanol was addedto the residue to neutralize; and the solvent was distilled off againunder reduced pressure. The residue was dissolved in tetrahydrofuran(4.0 ml)-methanol (4.0 ml); acetic acid (0.1 ml), 37% aqueousformaldehyde solution (0.5 ml) and sodium cyanoborohydride (90.5 mg,1.44 mmol) were added at room temperature; and the reaction mixture wasstirred for 1 hour. The reaction mixture was partitioned between ethylacetate and water; and the organic layer was washed with water andbrine, dried over anhydrous sodium sulfate. The solvent was distilledoff, and the residue was purified by NH silica gel column chromatography(eluent; ethyl acetate:methanol=98:2). The crystals were precipitatedfrom diethyl ether, filtered off, and dried under aeration to yield thetitle compound as white crystals (197.0 mg, 0.44 mmol, 60.7%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08-1.19 (5H, m), 1.30 (1H, m), 1.54(2H, m), 1.75 (2H, m), 2.09 (3H, m), 2.70 (2H, m), 2.98 (2H, m),3.20-3.40 (2H, m), 6.49 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz),6.85 (1H, s), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=3.6 Hz), 7.90(1H, d, J=2.4 Hz), 8.02 (1H, d, J=5.6 Hz), 8.08 (1H, m), 8.22 (1H, m),8.28 (1H, d, J=8.8 Hz), 9.00 (1H, s).

Example 61N1-Ethyl-5-(2-(((2-(diethylamino)ethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (140.9 mg, 0.32 mmol, 89.2%)was obtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (150mg, 0.36 mmol, Production example 27-2) and 2-(diethylamino)ethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.2 Hz), 1.17 (3H, t,J=7.2 Hz), 2.40-2.49 (6H, m), 3.13 (2H, m), 3.20-3.40 (2H, m), 6.49 (1H,dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.82 (1H, s), 7.03 (1H, dd,J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.90 (1H, d, J=3.6 Hz), 8.00(1H, d, J=5.6 Hz), 8.20-8.25 (2H, m), 8.28 (1H, d, J=8.8 Hz), 9.11 (1H,s).

Example 62N1-Ethyl-5-(2-(((2-(morpholin-4-yl)ethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (155.0 mg, 0.34 mmol, 95.1%)was obtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (150mg, 0.36 mmol, Production example 27-2) and 4-(2-aminoethyl)morpholine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.67 (3H, t, J=7.2 Hz), 2.30-2.40(6H, m), 3.20 (2H, m), 3.20-3.40 (2H, m), 3.54-3.57 (4H, m), 6.50 (1H,dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.03 (1H, dd,J=2.4, 8.8 Hz), 7.36 (1H, d, J=3.6 Hz), 7.90 (1H, d, J=2.4 Hz), 8.02(1H, d, J=5, 6 Hz), 8.10-8.25 (2H, m), 8.28 (1H, d, J=8.8 Hz), 9.11 (1H,s).

Example 63N1-Ethyl-5-(2-(((2-(4-hydroxypiperidino)ethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (49.1 mg, 0.11 mmol, 35.1%)was obtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (125mg, 0.30 mmol, Production example 27-2) and1-(2-aminoethyl)-4-hydroxypiperidine dihydrochloride.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.2 Hz), 1.36 (2H m),1.66-1.70 (2H, m), 2.00 (2H, m), 2.32 (2H, m), 2.65-2.69 (2H, m), 3.16(2H, m), 3.20-3.40 (2H, m), 3.40 (1H, m), 4.53 (1H, d, J=4.0 Hz), 6.50(1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.83 (1H, s), 7.03 (1H,dd. J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.90 (1H, d, J=3.6 Hz), 8.01(1H, d, J=5.6 Hz), 8.10-8.23 (2H, m), 8.28 (1H, d, J=8.8 Hz), 9.11 (1H,s).

Example 64N1-Methyl-5-(2-(((2-(4-hydroxypiperidino)ethyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (114.3 mg, 0.25 mmol, 25.3%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (402mg, 1.0 mmol, Production example 29-1) and1-(2-aminoethyl)-4-hydroxypiperidine dihydrochloride.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.32-1.38 (2H, m), 1.60-1.70 (2H, m),1.96-2.03 (2H, m), 2.31-2.34 (2H, m), 2.60-2.70 (2H, m), 2.83 (3H, d,J=4.4 Hz), 3.15-3.18 (2H, m), 3.42 (1H, m), 4.53 (1H, d, J=4.0 Hz), 6.51(1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.04 (1H,dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.01(1H, d, J=5.6 Hz), 8.14-8.16 (2H, m), 8.28 (1H, d, J=8.8 Hz), 9.11 (1H,s).

Example 65N1-Ethyl-5-(2-((3-(diethylamino)propylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (159.9 mg, 0.35 mmol, 98.1%)was obtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (150mg, 0.36 mmol, Production example 27-2) and 3-(diethylamino)propylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.91 (6H, t, J=7.2 Hz), 1.17 (3H, t,J=7.2 Hz), 1.50 (2H, m), 2.32-2.41 (6H, m), 3.10 (2H, m), 3.20-3.40 (2H,m), 6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.81 (1H, s),7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=3.6 Hz), 7.90 (1H, d, J=2.4Hz), 8.00 (1H, d, J=5.6 Hz), 8.12 (1H, m), 8.22 (1H, t, J=5.2 Hz), 8.28(1H, d, J=8.8 Hz), 9.03 (1H, s).

Example 66N1-Ethyl-5-(2-(((3-(morpholin-4-yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (135.0 mg, 0.29 mmol, 96.4%)was obtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (125mg, 0.30 mmol, Production example 27-2) and 4-(3-aminopropyl)morpholine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.2 Hz), 1.55 (2H, m),2.20-2.40 (6H, m), 3.11 (2H, m), 3.20-3.40 (2H, m), 3.51-3.55 (4H, m),6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.03(1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.90 (1H, d, J=3.6 Hz),8.01 (1H, d, J=5.6 Hz), 8.04 (1H, m), 8.21 (1H, t, J=5.6 Hz), 8.28 (1H,d, J=8.8 Hz), 9.02 (1H, s).

Example 67N1-Ethyl-5-(2-(((3-(4-methylpiperazin-1-yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (141.9 mg, 0.30 mmol, 98.6%)was obtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (125mg, 0.30 mmol, Production example 27-2) and1-(3-aminopropyl)-4-methylpiperazine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.2 Hz), 1.54 (2H, m),2.11 (3H, s), 2.11-2.40 (10H, m), 3.08 (2H, m), 3.20-3.40 (2H, m), 6.50(1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.03 (1H,dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.90 (1H, d, J=3.6 Hz), 8.01(1H, d, J=5.6 Hz), 8.04 (1H, m), 8.22 (1H, t, J=5.6 Hz), 8.28 (1H, d,J=8 8 Hz), 9.01 (1H, s).

Example 68N1-Cyclopropyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Tetrahydrofuran (30 ml) and triethylamine (3.87 ml, 27.8 mmol) wereadded to N1-cyclopropyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide(2.85 g, 9.25 mmol, CAS No. 417722-12-4) which was described in WO02/32872; phenyl chloroformate (2.57 ml, 20.4 mmol) was added thereto at0° C. while stirred; and the reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was partitioned betweenethyl acetate and water; and the organic layer was concentrated to yield3.30 g of the mixture of phenylN-(4-(1-(cyclopropylamino)carbonyl-1H-5-indolyl)-oxy-2-pyridyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate.A portion of 0.524 g of the mixture was dissolved inN,N-dimethylformamide (5 ml); 4-(1-pyrrolidinyl)piperidine (0.736 g,4.80 mmol) was added thereto; the reaction mixture was stirred for 5hours; the reaction mixture was partitioned between ethyl acetate andwater; and the organic layer was concentrated to yield the titlecompound as white crystals (280 mg, 0.57 mmol).

MS Spectrum (ESI): 489 (M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.57-0.75 (4H, m), 1.18-1.30 (2H, m),1.58-1.80 (6H, m), 2.03-2.12 (1H, m), 2.38-2.48 (4H, m), 2.72-2.87 (3H,m), 3.88-3.96 (2H, m), 6.53 (1H, dd, J=2.7, 6.1 Hz), 6.64 (1H, d, J=3.4Hz), 7.03 (1H, dd, J=2.7, 8.9 Hz), 7.30 (1H, d, J=2.7 Hz), 7.35 (1H, d,J=2.7 Hz), 7.86 (1H, d, J=3.4 Hz), 8.06 (1H, d, J=6.1 Hz), 8.24-8.29(2H, m), 9.08 (1H, s).

Example 695-(2-(3-((1R)-1-Hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid cyclopropylamide

Similarly to Example 5, the title compound (113 mg, 0.229 mmol) wasobtained as white crystals from a mixture (165 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate,intermediates in Example 68, and(2R)-2-amino-3-hydroxy-1-(pyrrolidin-1-yl)propan-1-one (265 mg, 1.67mmol, synthesized as an intermediate in Example 55).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58-0.66 (2H, m), 0.70-0.78 (2H, m),1.72-1.90 (4H, m), 2.78 (1H, m), 3.20-3.60 (6H, m), 4.54 (1H, m), 4.98(1H, t, J=5.6 Hz), 6.53 (1H, dd, J=2.0, 6.0 Hz), 6.67 (1H, d, J=3.6 Hz),6.97 (1H, d, J=2.0 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.37 (1H, d, J=2.4Hz), 7.88 (1H, d, J=3.6 Hz), 8.05 (1H, d, J=6.0 Hz), 8.16 (1H, brs),8.25-8.34 (2H, m), 9.18 (1H, s).

Example 705-(2-(3-((1S)-1-Hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid cyclopropylamide

Similarly to Example 5, the title compound (117 mg, 0.237 mmol) wasobtained as white crystals from a mixture (165 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate,intermediates in Example 68, and(2S)-2-amino-3-hydroxy-1-(pyrrolidin-1-yl)propan-1-one hydrochloride(synthesized as an intermediate in Example 18).

Example 715-(2-(3-(2-Oxo-2-(pyrrolidin-1-yl)ethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid cyclopropylamide

Similarly to Example 5, the title compound (90.9 mg, 0.197 mmol) wasobtained as white crystals from a mixture (165 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate,intermediates in Example 68, and 2-amino-1-(pyrrolidin-1-yl)ethanonehydrochloride (247 mg, 1.50 mmol, synthesized as an intermediate inExample 7).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58-0.66 (2H, m), 0.71-0.79 (2H, m),1.72-1.80 (2H, m), 1.83-1.91 (2H, m), 2.78 (1H, m), 3.28-3.40 (4H, m),3.89 (2H, d, J=4.4 Hz), 6.54 (1H, dd, J=2.0, 6.0 Hz), 6.67 (1H, d, J=3.6Hz), 6.94 (1H, d, J=2.0 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.38 (1H, d,J=2.4 Hz), 7.88 (1H, d, J=3.6 Hz), 8.05 (1H, d, J=6.0 Hz), 8.17 (1H,brs), 8.26-8.35 (2H, m), 9.28 (1H, s).

Example 725-(2-(3-(3-Oxo-3-(pyrrolidin-1-yl)propyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid cyclopropylamide

Similarly to Example 5, the title compound (113 mg, 0.237 mmol) wasobtained as white crystals from a mixture (165 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate,intermediates in Example 68, and 3-amino-1-(pyrrolidin-1-yl)propan-1-onehydrochloride (268 mg, 1.50 mmol, synthesized as an intermediate inExample 25).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58-0.66 (2H, m), 0.71-0.79 (2H, m),1.70-1.79 (2H, m), 1.79-1.88 (2H, m), 2.40 (2H, t, J=6.4 Hz), 2.78 (1H,m), 3.24-3.38 (6H, m), 6.51 (1H, dd, J=2.0, 6.0 Hz), 6.67 (1H, d, J=3.8Hz), 6.93 (1H, d, J=2.0 Hz), 7.05 (1H, dd, J=2.4, 8.8 Hz), 7.37 (1H, d,J=2.4 Hz), 7.88 (1H, d, J=3.8 Hz), 7.98-8.10 (2H, m), 8.26-8.34 (2H, m),9.09 (1H, s).

Example 735-(2-(3-((1R)-1-Hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid cyclopropylamide

Similarly to Example 5, the title compound (106 mg, 0.209 mmol) wasobtained as white crystals from a mixture (165 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate,intermediates in Example 68, and(2R)-2-amino-3-hydroxy-1-(piperidin-1-yl)propan-1-one (228 mg, 1.32mmol, synthesized as an intermediate in Example 57).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58-0.66 (2H, m), 0.70-0.78 (2H, m),1.38-1.62 (6H, m), 2.79 (1H, m), 3.38-3.53 (6H, m), 4.75 (1H, m), 4.93(1H, t, J=5.8 Hz), 6.54 (1H, dd, J=2.0, 6.0 Hz), 6.67 (1H, d, J=3.6 Hz),6.97 (1H, d, J=2.0 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.37 (1H, d, J=2.4Hz), 7.88 (1H, d, J=3.6 Hz), 8.05 (1H, d, J=6.0 Hz), 8.10-8.34 (3H, m),9.20 (1H, s).

Example 745-(2-(3-((1S)-1-Hydroxymethyl-2-oxo-2-piperidin-1-ylethyl)ureido)pyridin-4-yloxy)-1H-indole-1-carboxylicacid cyclopropylamide

Similarly to Example 5, the title compound (66.8 mg, 0.132 mmol) wasobtained as white crystals from a mixture (82.3 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate,intermediates in Example 68, and(2S)-2-amino-3-hydroxy-1-(piperidin-1-yl)propan-1-one hydrochloride (156mg, 0.748 mmol, synthesized as an intermediate in Example 20).

Example 75N1-Phenyl-5-(2-(((3-(diethylamino)propyl)amino)carbonyl)amino-4-pyridyl)-oxy-1H-1-indolecarboxamide

The title compound was obtained fromN1-phenyl-5-(2-amino-4-pyridyl)oxy)-1H-1-indolecarboxamide (CAS No.417721-87-0) which was written in the description of WO 02/32872 and3-diethylaminopropylamine using a procedure analogous to that describedfor Example 28.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.91 (6H, t, J=7.2 Hz), 1.47-1.53(2H, m), 2.30-2.44 (6H, m), 3.05-3.14 (2H, m), 6.52 (1H, dd, J=6.0, 2.0Hz), 6.76 (1H, d, J=3.6 Hz), 6.84 (1H, d, J=2.0H), 7.09 (1H, dd, J=9.2,2.4 Hz), 7.13 (1H, t, J=7.6 Hz), 7.38 (2H, dd, J=7.6, 7.6 Hz), 7.42 (1H,d, J=2.4 Hz), 7.64 (2H, d, J=7.6 Hz), 8.02 (1H, d, J=6.0 Hz), 8.10-8.14(2H, m), 8.27 (1H, d, J=9.2 Hz), 9.05 (1H, brs), 10.10 (1H, brs).

Example 76N1-Phenyl-5-(2-(((3-(4-methylpiperazin-1-yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound was obtained fromN1-phenyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (CAS No.417721-87-0) which was described in WO 02/32872 and1-(3-aminopropyl)-4-methylpiperazine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.52-1.59 (2H, m), 2.13 (3H, s),2.15-2.45 (10H, m), 3.08-3.15 (2H, m), 6.54 (1H, dd, J=6.0, 2.0 Hz),6.79 (1H, d, J=3.6 Hz), 6.89 (1H, brs), 7.10 (1H, dd, J=2.4, 9.2 Hz),7.15 (1H, t, J=7.6 Hz), 7.40 (2H, t, J=7.6 Hz), 7.44 (1H, d, J=2.4 Hz),7.66 (2H, d, J=7.6 Hz), 8.03-8.07 (2H, m), 8.14 (1H, d, J=3.6 Hz), 8.29(1H, d, J=9.2 Hz), 9.05 (1H, brs), 10.10 (1H, brs).

Example 77N1-Ethyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Tetrahydrofuran (20 ml) and triethylamine (2.70 ml, 19.4 mmol) wereadded to N1-ethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (1.91g, 6.45 mmol, Production example 27-1); phenyl chloroformate (1.79 ml,14.2 mmol) was added thereto at 0° C. while stirred; and the reactionmixture was stirred at room temperature for 2 hours. The reactionmixture was partitioned between ethyl acetate and water; the organiclayer was concentrated to yield a mixture (2.95 g) of phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate andphenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate.A portion of 0.454 g of the mixture was dissolved inN,N-dimethylformamide (5 ml); and 4-(1-pyrrolidinyl)piperidine (0.522 g,3.39 mmol) was added; and the reaction mixture was stirred for 5 hours.The reaction mixture was partitioned between ethyl acetate and water;the organic layer was concentrated to yield a solid; the obtained solidwas washed with hexane:diethyl ether=1:1 to yield the title compound ascrystals (205 mg, 0.43 mmol). MS Spectrum (ESI): 477 (M+1), 953 (2M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.12-1.22 (5H, m), 1.57-1.81 (6H, m),2.05-2.15(1H, m), 2.38-2.50 (4H, m), 2.77-2.78 (2H, m), 3.28-3.37 (2H,m), 3.87-3.97(2H, m), 6.53(1H, dd, J=2.5, 5.4 Hz), 6.66 (1H, d, J=3.5Hz), 7.02 (1H, dd, J=2.5, 8.9 Hz), 7.30 (1H, d, J=2.5 Hz), 7.36 (1H, d,J=2.5 Hz), 7.89 (1H, d, J=3.5 Hz), 8.05 (1H, d, J=5.4 Hz), 8.20 (1H, m),8.27 (1H, t, J=8.9 Hz), 9.08 (1H, s).

Example 785-(2-(((4-Hydroxy-4-methylpiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylicacid ethylamide

Similarly to Example 41, the title compound was obtained as colorlesscrystals (124 mg, 0.283 mmol, 89.4%) from 4-hydroxy-4-methylpiperidinemonohydrochloride (216 mg, 1.42 mmol, Production example 8-3) and phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(170 mg, 0.317 mmol, Production example 55-1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, s), 1.17 (3H, t, J=7.2 Hz),1.38-1.44 (4H, m), 3.13 (2H, m), 3.30 (2H, m), 3.63 (2H, m), 4.27 (1H,s), 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd,J=2.4, 8.8 Hz), 7.32 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.90(1H, d, J=3.0 Hz), 8.05 (1H, d, J=6.0 Hz), 8.21 (1H, t, J=5.4 Hz), 8.27(1H, d, J=8.8 Hz), 9.04 (1H, s).

Example 79N1-Ethyl-5-(2-((4-hydroxypiperidin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound was obtained as white powder(18.7 mg, 0.044 mmol, 14.7%) from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (125mg, 0.30 mmol, Production example 27-2) and 4-hydroxypiperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.13-1.27 (5H, m), 1.63-1.67 (2H, m),2.98 (2H, m), 3.20-3.40 (2H, m), 3.60 (1H, m), 3.74 (2H, m), 4.64 (1H,d, J=4.4 Hz), 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03(1H, dd, J=2.4, 8.8 Hz), 7.31 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz),7.90 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.6 Hz), 8.21 (1H, t, J=5.2 Hz),8.27 (1H, d, J=8.8 Hz), 9.09 (1H, s).

Example 80N1-Ethyl-5-(2-(piperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

N,N-Dimethylformamide (4 ml) and piperidine (0.31 ml, 3.13 mmol) wereadded to a mixture (0.336 g) of phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate andphenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateobtained in Example 77; the reaction mixture was stirred overnight; thereaction mixture was partitioned between ethyl acetate and water; andthe organic layer was concentrated to yield the title compound ascrystals (182 mg, 0.45 mmol).

MS Spectrum (ESI): 408 (M+1), 815 (2M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18 (3H, t, J=7.6 Hz), 1.35-1.57(6H, m), 3.23-3.33 (6H, m), 6.52 (1H, dd, J=2.4, 5.4 Hz), 6.67 (1H, d,J=3.4 Hz), 7.03 (1H, dd, J=2.4, 8.7 Hz), 7.30 (1H, d, J=2.4 Hz), 7.36(1H, d, J=2.4 Hz), 7.90 (1H, d, J=3.4 Hz), 8.06 (1H, d, J=5.5 Hz), 8.21(1H, t, J=5.5 Hz), 8.27 (1H, d, J=8.7 Hz), 9.05 (1H, s).

Example 81N1-Ethyl-5-((2-((pyrrolidin-1-ylcarbonyl)amino)-4-pyridyl)oxy)-1H-1-indolecarboxamide

N,N-Dimethylformamide (5 ml) and pyrrolidine (0.36 ml, 4.3 mmol) wereadded to a mixture (0.461 g) of phenylN-(4-(1-(ethylamino)carbonyl)-1H-5-indolyl)oxy-2-pyridyl)carbamate andphenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamateobtained in Example 77; the reaction mixture was stirred overnight; thereaction mixture was partitioned between ethyl acetate and water; andthe organic layer was concentrated to yield the title compound ascrystals (245 mg, 0.623 mmol).

MS Spectrum (ESI): 394 (M+1), 787 (2M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.16 (3H, t, J=7.6 Hz), 1.70-1.82(4H, m), 3.22-3.40 (6H, m), 6.54 (1H, dd, J=2.4, 5.5 Hz), 6.67 (1H, d,J=3.4 Hz), 7.03 (1H, dd, J=2.4, 8.7 Hz), 7.35 (1H, d, J=2.4 Hz), 7.41(1H, d, J=2.4 Hz), 7.90 (1H, d, J=3.4 Hz), 8.06 (1H, d, J=5.5 Hz), 8.21(1H, t, J=5.5 Hz), 8.27 (1H, d, J=8.7 Hz), 8.59 (1H, s).

Example 82N4-(4-((1-(Ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-4-morpholinecarboxamide

N,N-Dimethylformamide (5 ml) and morpholine (0.326 ml, 3.73 mmol) wereadded to a mixture (0.401 g) of phenylN-(4-(1-(ethylamino)carbonyl)-1H-5-indolyl)oxy-2-pyridyl)carbamate andphenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamateobtained in Example 77; the reaction mixture was stirred overnight; thereaction mixture was partitioned between ethyl acetate and water; theorganic layer was concentrated; and the obtained solid was washed with asolvent mixture of hexane:diethyl ether=1:1 to yield the title compound(255 mg, 0.62 mmol).

MS Spectrum (ESI): 410 (M+1), 819 (2M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.7 Hz), 3.25-3.42(6H, m), 3.48-3.53 (4H, m), 6.55 (1H, dd, J=2.6, 5.6 Hz), 6.67 (1H, d,J=3.6 Hz), 7.02 (1H, dd, J=2.6, 8.7 Hz), 7.29 (1H, d, J=2.6 Hz), 7.35(1H, d, J=2.4 Hz), 7.90 (1H, d, J=3.6 Hz), 8.08 (1H, d, J=5.6 Hz), 8.20(1H, t, J=5.6 Hz), 8.28 (1H, t, J=5.6 Hz), 9.19 (1H, s).

Example 83N1-Ethyl-5-(2-((1,1-dioxothiomorpholin-4-ylcarbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Similarly to Example 54, the title compound was obtained as colorlesscrystals (116 mg, 0.253 mmol, 80.0%) from 1,1-dioxothiomorpholinehydrochloride (248 mg, 1.42 mmol, Production example 54-3) and phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(170 mg, 0.317 mmol, Production example 55-1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.2 Hz), 3.10 (4H, m),3.29 (2H, m), 3.80 (4H, m), 6.58 (1H, dd, J=2.0, 5.6 Hz), 6.67 (1H, d,J=3.4 Hz), 7.03 (1H, dd, J=2.0, 9.0 Hz), 7.31 (1H, d, J=2.0 Hz), 7.36(1H, d, J=2.0 Hz), 7.90 (1H, d, J=3.4 Hz), 8.10 (1H, d, J=5.6 Hz), 8.22(1H, t, J=5.4 Hz), 8.28 (1H, d, J=9.0 Hz), 9.54 (1H, s).

Example 84N1-Ethyl-5-(2-((methoxylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound was obtained as whitecrystals (94.3 mg, 0.26 mmol, 70.9%) from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolylyl)oxy-2-pyridinyl)carbamate(150 mg, 0.36 mmol, Production example 27-2) and methoxylaminehydrochloride.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.2 Hz), 3.20-3.40(2H, m), 3.59 (3H, s), 6.57 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6Hz), 7.05 (1H, dd, J=2.4, 8.8 Hz), 7.16 (1H, s), 7.38 (1H, d, J=2.4 Hz),7.90 (1H, d, J=3.6 Hz), 8.08 (1H, d, J=5.6 Hz), 8.21 (1H, m), 8.28 (1H,d, J=8.8 Hz), 8.95 (1H, s), 10.15 (1H, s).

Example 85N1-Cyclopropyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

N,N-Dimethylformamide (5 ml) and 4-hydroxypiperidine (433 mg, 4.29 mmol)were added to a mixture (470 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamateobtained in Example 68; the reaction mixture was stirred overnight; thereaction mixture was partitioned between ethyl acetate and water; andthe organic layer was concentrated to yield the title compound as whitecrystals (220 mg, 0.51 mmol, 39%).

MS Spectrum (ESI): 436 (M+1), 871 (2M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58-0.63 (2H, m), 0.69-0.76 (2H, m),1.18-1.30 (2H, m), 1.60-1.70 (2H, m), 2.70-2.80 (1H, m), 2.93-3.02 (2H,m), 3.55-3.64 (1H, m), 3.69-3.77 (2H, m), 4.63 (1H, d, J=4.4 Hz), 6.53(1H, dd, J=2.4, 5.8 Hz), 6.64 (1H, d, J=3.6 Hz), 7.04 (1H, dd, J=2.4,8.5 Hz), 7.31 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.86 (1H, d,J=3.6 Hz), 8.06 (1H, d, J=5.8 Hz), 8.24-8.29 (2H, m), 9.08 (1H, s).

Example 86N1-Cyclopropyl-5-(2-(((4-hydroxy-4-methylpiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Similarly to Example 41, the title compound was obtained as colorlesscrystals (109 mg, 0.242 mmol) from 4-hydroxy-4-methylpiperidinemonohydrochloride (221 mg, 1.46 mmol, Production example 8-3) and amixture (200 mg, intermediates in Example 68) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.61 (2H, m), 0.73 (2H, m), 1.08 (3H,s), 1.30-1.41 (4H, m), 2.76 (1H, m), 3.14 (2H, m), 3.63 (2H, m), 4.27(1H, s), 6.53 (1H, d, J=5.4 Hz), 6.65 (1H, d, J=3.4 Hz), 7.03 (1H, d,J=8.8 Hz), 7.32 (1H, s), 7.35 (1H, s), 7.86 (1H, d. J=3.4 Hz), 8.06 (1H,d, J=5.4 Hz), 8.27 (2H, m), 9.04 (1H, s).

Example 87N4-(4-(1-(Cyclopropylamino)carbonyl)-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide

N,N-Dimethylformamide (5 ml) and morpholine (0.373 ml, 4.28 mmol) wereadded to a mixture (470 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamateobtained in Example 68; and the reaction mixture was stirred overnight;the reaction mixture was partitioned between ethyl acetate and water;the organic layer was concentrated; and the obtained solid was washedwith a solvent mixture of hexane:diethyl ether=1:1 to yield the titlecompound (255 mg, 0.58 mmol, 95%).

MS Spectrum (ESI): 422 (M+1), 843 (2M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58-0.75 (4H, m), 2.72-2.81 (1H, m),3.26-3.40 (4H, m), 3.50 (4H, t, J=4.8 Hz), 6.56 (1H, dd, J=2.5, 5.6 Hz),6.65 (1H, d, J=3.4 Hz), 7.04 (1H, dd. J=2.5, 8.8 Hz), 7.30 (1H, d, J=2.5Hz), 7.36 (1H, d, J=2.5 Hz), 7.86 (1H, d, J=3.4 Hz), 8.08 (1H, d, J=5.5Hz), 8.24-8.30 (2H, m), 9.18 (1H, s).

Example 88N1-Cyclopropyl-5-(2-((pyrrolidin-1-ylcarbonyl)amino)-4-pyridyl)oxy-1H-1-indolecarboxamide

N,N-Dimethylformamide (5 ml) and pyrrolidine (0.35 ml, 4.2 mmol) wereadded to a mixture (470 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamateobtained in Example 68; the reaction mixture was stirred overnight; thereaction mixture was partitioned between ethyl acetate and water; andthe organic layer was concentrated to yield the title compound as whitecrystals (200 mg, 0.49 mmol).

MS Spectrum (ESI): 406 (M+1), 811 (2M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58-0.78 (4H, m), 1.70-1.83 (4H, m),2.73-2.81 (1H, m), 3.23-3.45 (4H, m), 6.55 (1H, dd, J=2.2, 5.7 Hz), 6.65(1H, d, J=3.5 Hz), 7.03 (1H, dd, J=2.2, 8.7 Hz), 7.36 (1H, d, J=2.2 Hz),7.41 (1H, d, J=2.2 Hz), 7.86 (1H, d, J=3.5 Hz), 8.06 (1H, d, J=5.7 Hz),8.16-8.30 (2H, m), 8.59 (1H, s).

Example 89N1-Cyclopropyl-5-(2-(piperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

N,N-Dimethylformamide (5 ml) and piperidine (0.42 ml, 4.2 mmol) wereadded to a mixture (467 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamateobtained in Example 68; and the reaction mixture was stirred overnight;the reaction mixture was partitioned between ethyl acetate and water;the organic layer was concentrated; the obtained solid was washed with asolvent mixture of hexane: diethyl ether 1:1 to yield the title compoundas crystals (241 mg, 0.57 mmol).

MS Spectrum (ESI): 420 (M+1), 839 (2M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58-0.77 (4H, m), 1.34-1.55 (6H, m),2.72-2.81 (1H, m), 3.27-3.40 (4H, m), 6.52 (1H, dd, J=2.6, 5.6 Hz), 6.64(1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.6, 8.7 Hz), 7.30 (1H, d, J=2.6 Hz),7.35 (1H, d, J=2.6 Hz), 7.87 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.6 Hz),8.23-8.30 (2H, m), 9.03 (1H, s).

Example 90N4-(4-(1-(Cyclopentylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide

PhenylN-(4-(1-cyclopentylaminocarbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(200 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (1.5 ml) andmorpholine (0.15 ml, 1.73 mmol); and the reaction mixture was stirred atroom temperature overnight. The reaction mixture was partitioned betweenethyl acetate and water; and the organic layer was washed with brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Fuji Silysia BW-300; ethyl acetate, ethyl acetate:methanol=10:1 in thisorder); the obtained colorless oil was crystallized by addition ofdiethyl ether; and the crystals were filtered off, washed with diethylether, and dried under aeration to yield the title compound as colorlesscrystals (140 mg, 0.31 mmol, 90%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.48-1.64 (4H, m), 1.66-1.76 (2H, m),1.88-1.98 (2H, m), 3.35 (4H, m), 3.51 (4H, m), 4.14 (1H, m), 6.56 (1H,d, J=6.0 Hz), 6.65 (1H, d, J=3.6 Hz), 7.02 (1H, d, J=8.8 Hz), 7.30 (1H,s), 7.35 (1H, s), 7.96 (1H, d, J=3.6 Hz), 8.00 (1H, d, J=6.8 Hz), 8.08(1H, d, J=6.0 Hz), 8.25 (1H, d, J=8.8 Hz), 9.18 (1H, s).

The starting materials were synthesized as follows.

Production Example 90-1 Phenyl N-cyclopentylcarbamate

Cyclopentylamine (9.9 ml, 100 mmol) was dissolved in tetrahydrofuran(400 ml); pyridine (8.9 ml, 110 mmol) was added thereto; and thereaction mixture was stirred. The reaction mixture was cooled with ice;phenyl chloroformate (13.8 ml, 110 mmol) was added dropwise for 5minutes while stirring; and the reaction mixture was stirred at roomtemperature for 24.5 hours. The reaction mixture was partitioned betweenethyl acetate and water; and the organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The obtained crystals were suspended in a solvent mixture ofhexane:ethyl acetate=5:1, filtered off, washed with hexane, and driedunder aeration to yield the title compound as colorless crystals (16.6g, 81 mmol, 81%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.47 (4H, m), 1.63 (2H, m), 1.81 (2H,m), 3.81 (1H, m), 7.07 (2H, d, J=7.6 Hz), 7.17 (1H, t, J=7.6 Hz), 7.35(2H, t, J=7.6 Hz), 7.75 (1H, d, J=6.8 Hz).

Production Example 90-2N1-Cyclopentyl-5-(2-aminopyridin-4-yloxy)-1H-1-indolecarboxamide

4-(1H-5-Indolyloxy)-2-pyridinamine (2.50 g, 11.1 mmol, CAS No.417722-11-3), which was described in WO 02/32872, was dissolved inN,N-dimethylformamide (30 ml); sodium hydride (0.530 g, 13.3 mmol) wasadded thereto at room temperature; and the reaction mixture was stirredfor 30 minutes. Phenyl N-cyclopentylcarbamate (2.50 g, 12.2 mmol) wasadded thereto at room temperature while stirring; and the reactionmixture was stirred for 30 minutes. Water was added to the reactionmixture; and the precipitated crystals were filtered off, and washedwith water. This crystals were dissolved in methanol, and purified bysilica gel column chromatography (Fuji Silysia NH; hexane:ethylacetate=1:1, ethyl acetate, ethyl acetate:methanol=98:2 in this order).The obtained crystals were suspended in hexane: ethanol=10:1, filteredoff, washed with hexane, and dried under aeration to yield the titlecompound as colorless crystals (2.08 g, 6.18 mmol, 55.7%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.56 (4H, m), 1.71 (2H, m), 1.92 (2H,m), 4.14 (1H, m), 5.74 (1H, d, J=2.0 Hz), 5.83 (2H, s), 6.12 (1H, dd,J=2.0, 5.6 Hz), 6.64 (1H, d, J=3.4 Hz), 7.00 (1H, dd, J=2.0, 8.8 Hz),7.32 (1H, d, J=2.0 Hz), 7.75 (1H, d, J=5.6 Hz), 7.94 (1H, d, J=3.4 Hz),7.97 (1H, d, J=6.4 Hz), 8.23 (1H, d, J=8.8 Hz).

Production Example 90-3 PhenylN-(4-(1-cyclopentylaminocarbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate

N1-Cyclopentyl-5-(2-aminopyridin-4-yloxy)-1H-1-indolecarboxamide (1.55g, 4.58 mmol) was dissolved in tetrahydrofuran (90 ml); triethylamine(1.43 ml, 10.31 mmol) and pyridine (0.56 ml, 6.88 mmol) were addedthereto; and the reaction mixture was stirred. The reaction mixture wascooled with ice; phenyl chloroformate (1.44 ml, 11.45 mmol) was addeddropwise; and the reaction mixture was stirred at room temperature for2.5 hours. The reaction mixture was partitioned between ethyl acetateand water; and the organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (Fuji SilysiaBW-300; hexane:ethyl acetate=1:1, 1:3 in this order) to yield the titlecompound as a colorless amorphous solid (2.516 g, 4.36 mmol, 95.2%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.50-1.63 (4H, m), 1.66-1.74 (2H, m),1.88-1.98 (2H, m), 4.15 (1H, m), 6.65 (1H, d, J=3.8 Hz), 6.95 (1H, dd,J=2.4, 5.6 Hz), 7.09 (1H, dd, J=2.4, 8.8 Hz), 7.16 (4H, d, J=7.6 Hz),7.29 (2H, d, J=7.6 Hz), 7.42 (4H, d, J=7.6 Hz), 7.44 (1H, d, J=2.4 Hz),7.51 (1H, d, J=2.4 Hz), 7.98 (1H, d, J=3.8 Hz), 8.01 (1H, d, J=6.8 Hz),8.28 (1H, d, J=8.8 Hz), 8.42 (1H, d, J=5.6 Hz).

Example 915-(2-(((4-Hydroxypiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-indole-1-carboxylicacid cyclopentylamide

Similarly to Example 90, the title compound was obtained as colorlesscrystals (129 mg, 0.278 mmol, 80.2%) from phenylN-(4-(1-cyclopentylaminocarbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(200 mg, 0.346 mmol, Production example 90-3) and 4-hydroxypiperidine(175 mg, 1.73 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.23 (2H, m), 1.48-1.77 (8H, m), 1.92(2H, m), 2.98 (2H, m), 3.59 (1H, m), 3.73 (2H, m), 4.15 (1H, m), 4.64(1H, d, J=4.4 Hz), 6.53 (1H, dd, J=2.0, 5.6 Hz), 6.65 (1H, d, J=3.6 Hz),7.02 (1H, dd, J=2.0, 9.0 Hz), 7.31 (1H, d, J=2.0 Hz), 7.35 (1H, d, J=2.0Hz), 7.96 (1H, d, J=3.6 Hz), 7.99 (1H, d, J=6.8 Hz), 8.06 (1H, d, J=5.6Hz), 8.24 (1H, d, J=9.0 Hz), 9.09 (1H, s).

Example 92N1-Cyclopentyl-5-(2-((4-(pyrrolidin-1-yl)piperidin-1-ylcarbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Similarly to Example 90, the title compound was obtained as colorlesscrystals (83 mg, 0.161 mmol, 46.3%) from phenylN-(4-(1-cyclopentylaminocarbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(200 mg, 0.346 mmol, Production example 90-3) and4-(1-pyrrolidinyl)piperidine (268 mg, 1.73 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18-1.30 (2H, m), 1.50-1.80 (12H,m), 1.87-1.98 (2H, m), 2.08 (1H, m), 2.43 (4H, m), 2.81 (2H, m), 3.91(2H, m), 4.15 (1H, m), 6.53 (1H, dd, J=2.0, 5.6 Hz), 6.65 (1H, d, J=3.6Hz), 7.02 (1H, dd, J=2.0, 9.0 Hz), 7.31 (1H, d, J=2.0 Hz), 7.35 (1H, d,J=2.0 Hz), 7.96 (1H, d, J=3.6 Hz), 7.99 (1H, d, J=6.8 Hz), 8.06 (1H, d,J=5.6 Hz), 8.25 (1H, d, J=9.0 Hz), 9.08 (1H, s).

Example 93N1-(3-Methylbutyl)-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

N,N-dimethylformamide (30 ml), pyridine (0.52 ml, 6.4 mmol) andtriethylamine (1.35 ml, 9.69 mmol) were added toN1-(3-methylbutyl)-5-((2-amino-4-pyridyl)oxy)-1H-1-indolecarboxamide(1.45 g, 4.29 mmol); phenyl chloroformate (0.81 ml, 6.4 mmol) was addedat 0° C. while stirring; and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was partitioned betweenethyl acetate and water; and the organic layer was concentrated andsubjected to silica gel column chromatography to yield a mixture (2.0 g)of phenylN-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamateand phenylN-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate.A portion of 0.4 g of the mixture was dissolved in N,N-dimethylformamide(4 ml); 4-(1-pyrrolidinyl)piperidine (0.43 g, 2.8 mmol) was addedthereto; and the reaction mixture was stirred for 2 hours. The reactionmixture was partitioned between ethyl acetate and water; the organiclayer was concentrated; and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) toyield the title compound as white crystals (275 mg, 0.53 mmol).

MS Spectrum (ESI): 519(M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.91 (6H, d, J=7.6 Hz), 1.18-1.30(3H, m), 1.47 (2H, q, J=7.6 Hz), 1.57-1.80 (6H, m), 2.03-2.22 (1H, m),2.37-2.48 (4H, m), 2.76-2.85 (2H, m), 3.25-3.36 (2H, m), 3.88-3.97 (2H,m), 6.53 (1H, dd, J=2.4, 5.4 Hz), 6.66 (1H, d, J=3.6 Hz), 7.02 (1H, dd,J=2.4, 8.7 Hz), 7.31 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.90(1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.4 Hz), 8.16 (1H, t, J=5.4 Hz), 8.27(1H, d, J=8.7 Hz), 9.08 (1H, s).

The starting materials were synthesized as follows.

Production Example 93-1N1-(3-Methylbutyl)-5-((2-amino-4-pyridyl)oxy)-1H-1-indolecarboxamide

4-(1H-5-Indolyloxy)-2-pyridinamine (2.0 g, 8.9 mmol, CAS No.417722-11-3) which was described in WO 02/32872 was dissolved inN,N-dimethylformamide (20 ml); and sodium hydride (426 mg, 10.7 mmol)was added thereto at room temperature while stirring. The reactionmixture was cooled with ice bath after 30 minutes; phenylN-(3-methylbutyl)carbamate (2.02 g, 9.75 mmol) was added thereto; andthe reaction mixture was stirred for 3 hours at room temperature. Thereaction mixture was partitioned between ethyl acetate and water; theorganic layer was washed with water and brine, dried over anhydroussodium sulfate, and concentrated; and the residue was purified byNH-silica gel column chromatography (hexane:ethyl acetate=3:1) to yieldthe title compound as crystals (1.45 g, 4.3 mmol, 48%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.89-0.93 (6H, m), 1.40-1.70 (3H, m),3.25-3.40 (2H, m), 5.72-5.75 (1H, m), 5.83 (2H, s), 6.10-6.40 (1H, m),6.64-6.68 (1H, m), 6.98-7.02 (1H, m), 7.30-7.34 (1H, m), 7.75 (1H, dd,J=1.5, 6.0 Hz), 7.86-7.90 (1H, m), 8.14 (1H, t, J=4.5 Hz), 8.25 (1H, d,J=9.0 Hz).

Production Example 93-2 Phenyl N-(3-methylbutyl)carbamate

Phenyl chloroformate (14.8 ml, 0.117 mol) was dissolved intetrahydrofuran (200 ml); triethylamine (18.0 ml, 0.129 mol) andisoamylamine (15.0 ml, 0.129 mol) were added thereto at room temperaturewhile stirring; and the reaction mixture was stirred overnight. Thereaction mixture was partitioned between ethyl acetate and water; andthe organic layer was concentrated and dried under reduced pressure toyield the title compound as crystals (14 g, 0.068 mol, 58%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.89 (6H, d, J=7.9 Hz), 1.36 (2H, q,J=7.9 Hz), 1.55-1.69 (1H, m), 3.05 (2H, q, J=7.9 Hz), 7.03-7.09 (2H, m),7.14-7.19 (1H, m), 7.31-7.38 (2H, m), 7.68 (1H, t, J=4.8 Hz).

Example 94N1-(3-Methylbutyl)-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

N,N-dimethylformamide (2.5 ml) and 4-hydroxypiperidine (213 mg, 2.11mmol) were added to a mixture (243 mg) of phenylN-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-carbamateand phenylN-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamatesynthesized in Example 93; and the reaction mixture was stirred for 2hours. The reaction mixture was partitioned between ethyl acetate andwater; the organic layer was concentrated; and the residue was purifiedby NH-silica gel column chromatography (ethyl acetate:methanol=10:1) toyield the title compound as white crystals (150 mg, 0.322 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.91 (6H, d, J=7.2 Hz), 1.18-1.30(2H, m), 1.46 (2H, q, J=7.2 Hz), 1.60-1.70 (3H, m), 2.97 (2H, m),3.25-3.35 (2H, m), 3.55-3.64 (1H, m), 3.69-3.80 (2H, m), 4.63 (1H, d,J=3.4 Hz), 6.53 (1H, dd, J=2.3, 5.8 Hz), 6.66 (1H, d, J=3.5 Hz), 7.02(1H, dd, J=2.3, 8.6 Hz), 7.31(1H, d, J=2.3 Hz), 7.35 (1H, d, J=2.3 Hz),7.90 (1H, d, J=3.5 Hz), 8.06 (1H, d, J=5.8 Hz), 8.16 (1H, t, J=5.8 Hz),8.26 (1H, t, J=8.6 Hz), 9.08 (1H, s).

Example 95N4-(4-(1-((3-Methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide

N,N-dimethylformamide (5 ml) and morpholine (0.163 ml, 1.87 mmol) wereadded to a mixture (0.6 g) of phenylN-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamateand phenylN-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamatesynthesized in Example 93; and the reaction mixture was stirred for 2hours. The reaction mixture was partitioned between ethyl acetate andwater; the organic layer was concentrated; and the residue was purifiedby silica gel column chromatography (Fuji Silysia NH, ethylacetate:methanol=10:1) to yield the title compound as white crystals(0.202 g, 0.447 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (6H, dd, J=1.7, 7.3 Hz), 1.47(2H, q, J=7.3 Hz), 1.58-1.70 (1H, m), 3.25-3.60 (10H, m), 6.55-6.59 (1H,m), 6.65-6.70 (1H, m), 7.00-7.07 (1H, m), 7.32 (1H, s), 7.37 (1H, m),7.90 (1H, m), 8.07 (1H, m), 8.17 (1H, t, J=5.2 Hz), 8.27 (1H, d, J=8.3Hz), 9.18 (1H, s).

Example 96N1-(1-Ethylpropyl)-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Tetrahydrofuran (20 ml) and triethylamine (1.73 ml, 12.4 mmol) wereadded toN1-(1-ethylpropyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (1.45g, 4.29 mmol); phenyl chloroformate (1.15 ml, 9.1 mmol) was addedthereto at 0° C. while stirring; and the reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was partitionedbetween ethyl acetate and water; and the organic layer was concentratedand subjected to silica gel column chromatography to yield a mixture(1.8 g) of phenylN-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamateand phenylN-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)-oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate.A portion of 0.6 g of the mixture was dissolved in N,N-dimethylformamide(5 ml); 4-(1-pyrrolidinyl)piperidine (0.7 g, 4.7 mmol) and stirred for 2hours; the reaction mixture was partitioned between ethyl acetate andwater; the organic layer was concentrated; and the residue was purifiedby silica gel column chromatography (Fuji Silysia NH, ethylacetate:methanol=10:1) to yield as white crystals (202 mg, 0.391 mmol).

MS Spectrum (ESI): 519(M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.90 (6H, t, J=7.5 Hz), 1.20-1.30(3H, m), 1.47-1.80 (9H, m), 2.03-2.12 (1H, m), 2.40-2.47 (4H, m),2.77-2.86 (2H, m), 3.62-3.72 (1H, m), 3.88-3.95 (2H, m), 6.53 (1H, dd,J=2.4, 5.9 Hz), 6.66 (1H, d, J=3.5 Hz), 7.02 (1H, dd, J=2.4, 8.8 Hz),7.11 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.78 (1H, d, J=8.8 Hz),7.99 (1H, d, J=3.5 Hz), 8.06 (1H, d, J=5.9 Hz), 8.25 (1H, t, J=8.8 Hz),9.08 (1H, s).

The starting materials were synthesized by following methods.

Production Example 96-1N1-(1-Ethylpropyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

4-(1H-5-Indolyloxy)-2-pyridinamine (1.85 g, 8.2 mmol, CAS No.417722-11-3) which was described in WO 02/32872 was dissolved inN,N-dimethylformamide (20 ml); and sodium hydride (394 mg, 9.84 mmol)was added thereto while stirring at room temperature. The reactionmixture was cooled with ice bath after 30 minutes; phenylN-(1-ethylpropyl)carbamate (1.87 g, 9.03 mmol); and the reaction mixturewas stirred at room temperature for 3 hours. The reaction mixture waspartitioned between ethyl acetate and water; the organic layer waswashed with water and brine, dried over anhydrous sodium sulfate,concentrated; and the residue was purified by silica gel columnchromatography (Fuji Silysia NH, hexane:ethyl acetate=3:1) to yield thetitle compound as crystals (1.95 g, 5.8 mmol, 71%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.89 (6H, t, J=7.5 Hz), 1.44-1.63(4H, m), 3.60-3.72 (1H, m), 5.73 (1H, d, J=2.6 Hz), 5.80 (2H, s), 6.12(1H, dd, J=2.6, 6.0 Hz), 6.67 (1H, d, J=4.3 Hz), 7.00 (1H, dd, J=2.6,8.6 Hz), 7.32 (1H, d, J=2.6 Hz), 7.75 (1H, d, J=6.0 Hz), 7.98 (1H, d,J=4.3 Hz), 8.23 (1H, d, J=8.6 Hz), 9.30 (1H, s).

Production Example 96-2 Phenyl N-(1-ethylpropyl)carbamate

1-Ethylpropylamine (11.6 ml, 100 mmol) was dissolved in tetrahydrofuran(400 ml); pyridine (8.9 ml, 110 mmol) was added thereto at roomtemperature; and the reaction mixture was stirred. The reaction mixturewas cooled with ice bath; phenyl chloroformate (13.8 ml, 110 mmol) wasadded dropwise; and the reaction mixture was stirred at room temperaturefor 24 hours. Water was added to the reaction mixture; the reactionmixture was partitioned between ethyl acetate and water; and the organiclayer was washed with brine, dried over anhydrous sodium sulfate, andthe solvent was distilled off under reduced pressure. The obtainedcrystals were washed with diethyl ether:hexane=1:5 to yield the titlecompound as crystals (22.3 g, 147 mmol, 59.1%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.87 (6H, t, J=7.5 Hz), 1.30-1.56(4H, m), 3.20-3.34 (1H, m), 7.03-7.08 (2H, m), 7.14-7.19 (1H, m),7.32-7.38 (2H, m), 7.51 (1H, d, J=8.7 Hz).

Example 97N1-(1-Ethylpropyl)-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

N,N-Dimethylformamide (4 ml) and 4-hydroxypiperidine (360 mg, 3.56 mmol)were added to a mixture (456 mg) of phenylN-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-carbamateand phenylN-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamatesynthesized in Example 96; and the reaction mixture was stirred for 2hours. The reaction mixture was partitioned between ethyl acetate andwater; the organic layer was concentrated; and the residue was purifiedby silica gel column chromatography (Fuji Silysia NH, ethylacetate:methanol=10:1) to yield the title compound as white crystals(1.37 mg, 0.294 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.90 (6H, t, J=7.5 Hz), 1.18-1.30(3H, m), 1.45-1.70 (6H, m), 2.92-3.02 (2H, m), 3.55-3.80 (3H, m), 4.63(1H, d, J=5.1 Hz), 6.53 (1H, m), 6.66 (1H, d, J=3.5 Hz), 7.02 (1H, dd,J=2.5, 8.8 Hz), 7.31 (1H, d, J=2.5 Hz), 7.36 (1H, d, J=2.5 Hz), 7.78(1H, d, J=8.8 Hz), 7.98 (1H, d, J=3.5 Hz), 8.06 (1H, d, J=5.7 Hz), 8.24(1H, t, J=8.8 Hz), 9.08 (1H, s).

Example 98N4-(4-(1-((1-Ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide

N,N-dimethylformamide (3 ml) and morpholine (0.22 ml, 2.5 mmol) wereadded to a mixture (0.324 g) of phenylN-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamateand phenylN-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamatesynthesized in Example 96; and the reaction mixture was stirred for 2hours. The reaction mixture was partitioned between ethyl acetate andwater; the organic layer was concentrated; and the residue was purifiedby silica gel column chromatography (Fuji Silysia NH, ethylacetate:methanol=10:1) to yield the title compound as white crystals (95mg, 0.21 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.91 (6H, t, J=7.5 Hz), 1.45-1.65(4H, m), 3.37-3.40 (4H, m), 3.48-3.58 (4H, m), 3.62-3.72 (1H, m), 6.56(1H, dd, J=2.6, 5.8 Hz), 6.68 (1H, d, J=3.5 Hz), 7.02 (1H, dd, J=2.6,8.8 Hz), 7.31 (1H, d, J=2.6 Hz), 7.36 (1H, d, J=2.6 Hz), 7.80 (1H, d,J=9.1 Hz), 8.00 (1H, d, J=3.5 Hz), 8.08 (1H, d, J=5.8 Hz), 8.26 (1H, d,J=8.8 Hz), 9.18 (1H, s).

Example 99N4-(4-(1-((1-Pentyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide

Similarly to Example 90, the title compound was obtained as colorlesscrystals (131 mg, 0.29 mmol, 84%) from phenylN-(4-(1-(1-pentylamino)carbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(200 mg, 0.35 mmol) and morpholine (0.15 ml, 1.7 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.88 (3H, t, J=6.0 Hz), 1.31 (4H, m),1.56 (2H, m), 3.26 (2H, m), 3.35 (4H, m), 3.51 (4H, m), 6.56 (1H, d,J=5.6 Hz), 6.67 (1H, d, J=3.0 Hz), 7.03 (1H, d, J=8.0 Hz), 7.31 (1H, s),7.36 (1H, s), 7.91 (1H, d, J=3.0 Hz), 8.08 (1H, d, J=5.6 Hz), 8.20 (1H,t, J=5.6 Hz), 8.26 (1H, d, J=8.0 Hz), 9.18 (1H, s).

The starting materials were synthesized by following procedures.

Production Example 99-1 Phenyl N-(1-pentyl)carbamate

Similarly to Example 90-1, the title compound was obtained as paleyellow crystals (20.5 g, 99 mmol, 99%) from 1-pentylamine (11.6 ml, 100mmol), pyridine (8.9 ml, 110 mmol) and phenyl chloroformate (13.8 ml,110 mmol).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 0.92 (3H, t, J=6.8 Hz), 1.36 (4H, m),1.58 (2H, m), 3.26 (2H, q, J=6.8 Hz), 5.00 (1H, brs), 7.13 (2H, d, J=7.6Hz), 7.19 (1H, t, J=7.6 Hz), 7.35 (2H, t, J=7.6 Hz).

Production Example 99-2N1-(1-Pentyl)-5-(2-aminopyridin-4-yloxy)-1H-1-indolecarboxamide

4-(1H-5-Indolyloxy)-2-pyridinamine (5.0 g, 22 mmol, CAS No. 417722-11-3)which was described in WO 02/32872 was dissolved inN,N-dimethylformamide (60 ml); sodium hydride (1.06 g, 27 mmol) wasadded thereto at room temperature; and the reaction mixture was stirredfor 30 minutes. Phenyl N-n-pentylcarbamate (5.06 g, 24 mmol) whilestirring at room temperature; and the reaction mixture was stirred for30 minutes. The reaction mixture was partitioned between water and ethylacetate (insoluble portions were perfectly dissolved by adding a smallamount of methanol); and the organic layer was washed with brine, driedover anhydrous sodium sulfate, concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (Fuji SilysiaNH; hexane:ethyl acetate=1:1, ethyl acetate, ethyl acetate:methanol=95:5in this order). The obtained crystals were suspended inhexane:ethanol=10:1, filtered off, washed with hexane, and dried underaeration to yield the title compound as colorless crystals (1.55 g, 4.58mmol, 21%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.87 (3H, t, J=6.6 Hz), 1.31 (4H m),1.56 (2H, m), 3.25 (2H, m), 5.74 (1H, d, J=2.8 Hz), 5.83 (2H, s), 6.12(1H, dd, J=2.8, 5.8 Hz), 6.65 (1H, d, J=3.6 Hz), 7.00 (1H, dd, J=2.0,8.8 Hz), 7.32 (1H, d, J=2.0 Hz), 7.75 (1H, d, J=5.8 Hz), 7.89 (1H, d,J=3.6 Hz), 8.17 (1H, t, J=5.4 Hz), 8.25 (1H, d, J=8.8 Hz).

Production Example 99-3 PhenylN-(4-((1-pentyl)aminocarbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate

Similarly to Example 90-3, the title compound was obtained as acolorless amorphous solid (2.39 g, 4.13 mmol, 90.1%) fromN1-(1-pentyl)-5-(2-aminopyridin-4-yloxy)-1H-1-indolecarboxamide (1.55 g,4.58 mmol), triethylamine (1.43 ml, 10.31 mmol), pyridine (0.56 ml, 6.88mmol), and phenyl chloroformate (1.44 ml, 11.45 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm) 0.87 (3H, t, J=6.4 Hz), 1.31 (4H, m),1.56 (2H, m), 3.27 (2H, m), 6.56 (1H, d, J=3.6 Hz), 6.96 (1H, dd, J=2.4,5.4 Hz), 7.09 (1H, dd, J=2.4, 9.0 Hz), 7.16 (4H, d, J=7.6 Hz), 7.29 (2H,t, J=7.6 Hz), 7.43 (5H, m), 7.51 (1H, d, J=2.4 Hz), 7.93 (1H, d, J=2.4Hz), 8.21 (1H, t, J=5.6 Hz), 8.31 (1H, d, J=9.0 Hz), 8.42 (1H, d, J=5.4Hz).

Example 100N1-(1-Pentyl)-5-(2-(((4-hydroxypiperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Similarly to Example 90, the title compound was obtained as colorlesscrystals (149 mg, 0.320 mmol, 92.6%) from phenylN-(4-(1-(1-pentyl)aminocarbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(200 mg, 0.346 mmol, Production example 99-3) and 4-hydroxypiperidine(174 mg, 1.73 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.87 (3H, m), 1.15-1.40 (6H, m),1.50-1.70 (4H, m), 2.98 (2H, m), 3.36 (2H, m), 3.59 (1H, m), 3.74 (2H,m), 4.64 (1H, d, J=4.0 Hz), 6.53 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6Hz), 7.03 (1H, d, J=8.6 Hz), 7.31 (1H, s), 7.35 (1H, s), 7.91 (1H, d,J=3.6 Hz), 8.06 (1H, d, J=5.2 Hz), 8.19 (1H, m), 8.26 (1H, d, J=8.6 Hz),9.09 (1H, s).

Example 101N1-(1-Pentyl)-5-(2-((4-(pyrrolidin-1-yl)piperidin-1-ylcarbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Similarly to Example 90, the title compound was obtained as colorlesscrystals (124 mg, 0.239 mmol, 69.2%) from phenylN-(4-(1-(1-pentyl)aminocarbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(200 mg, 0.346 mmol, Production example 99-3) and4-(1-pyrrolidinyl)piperidine (267 mg, 1.73 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.87 (3H, t, J=6.8 Hz), 1.20-1.35(6H, m), 1.52-1.67 (6H, m), 1.74 (2H, m), 2.08 (1H, m), 2.43 (2H, m),2.81 (2H, t, J=7.6 Hz), 3.23-3.29 (4H, m), 3.92 (2H, m), 6.53 (1H, dd,J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.8 Hz), 7.03 (1H, dd, J=2.4, 9.2 Hz),7.31 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.91 (1H, t, J=3.8 Hz),8.06 (1H, d, J=5.6 Hz), 8.19 (1H, d, J=5.4 Hz), 8.26 (1H, d, J=9.2 Hz),9.09 (1H, s).

Example 102N1-Methyl-3-chloro-5-(2-(((3-(diethylamino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

PhenylN-(4-(3-chloro-1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate(160 mg), 3-(diethylamino)propylamine (120 mg), N,N-dimethylformamide (5ml) were mixed together and stirred at room temperature for 10 minutes.After the addition of aqueous sodium hydrogencarbonate, extraction wasperformed with ethyl acetate. The purification by silica gel columnchromatography (Fuji Silysia NH, ethyl acetate and sequentially ethylacetate:methanol=10:1) to yield the title compound as a white solid (86mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.90 (6H, t, J=7.2 Hz), 1.46-1.56(2H, m), 2.32-2.46 (6H, m), 2.83 (3H, d, J=4.4 Hz), 3.08-3.15 (2H, m),6.52 (1H, dd, J=5.6, 2.4 Hz), 6.84 (1H, d, J=2.4 Hz), 7.16 (1H, dd,J=8.8, 2.4 Hz), 7.28 (1H, d, J=2.4 Hz), 8.02 (1H, d, J=5.6 Hz), 8.09(2H, s), 8.21 (1H, q, J=4.4 Hz), 8.33 (1H, d, J=8.8 Hz), 9.04 (1H, s).

The starting materials were synthesized as follows.

Production Example 102-1N1-Methyl-5-(2-amino-4-pyridyl)oxy-3-chloro-1H-indolecarboxamide

5-((2-amino-4-pyridyl)oxy)-3-chloro-1H-1-indole (4.0 g, 15 mmol, CAS No.417721-98-3) which was described in WO 02/32872 was dissolved inN,N-dimethylformamide (20 ml); sodium hydride (0.68 g, 60% in oil) andphenyl N-methylcarbamate (2.6 g, the product of Production example 2-1)were added thereto; and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was partitioned betweenethyl acetate and water; and the organic layer was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (Fuji Silysia NH, hexane:ethyl acetate=1:2) to yield thetitle compound as a colorless amorphous solid (1.5 g).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.83 (3H, d, J=4.0 Hz), 5.78 (1H, d,J=2.0 Hz), 5.88 (2H, brs), 6.14 (1H, dd, J=2.0, 5.8 Hz), 7.14 (1H, dd,J=2.4, 9.0 Hz), 7.23 (1H, d, J=2.4 Hz), 7.78 (1H, d, J=5.8 Hz), 8.08(1H, s), 8.19 (1H, m), 8.32 (1H, d, J=9.0 Hz).

Production Example 102-2 PhenylN-(4-(3-chloro-1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate

While a mixture ofN1-methyl-5-(2-amino-4-pyridyl)oxy-3-chloro-1H-1-indolecarboxamide (850mg, Production example 102-1), triethylamine (0.37 ml), pyridine (320mg) and N,N-dimethylformamide (10 ml) was cooled with ice and sodiumchloride, phenyl chloroformate (630 mg) was added dropwise to themixture. Aqueous solution of sodium hydrogencarbonate was added theretoafter stirring for 20 minutes; extraction was performed with ethylacetate; and purification was performed by silica gel columnchromatography (ethyl acetate). The crystals precipitated by addingethyl acetate to the residue were filtered off to yield the titlecompound as white crystals (160 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.80 (3H, d, J=4.4 Hz), 6.70 (1H, dd,J=5.6, 2.4 Hz), 7.10-7.25 (4H, m), 7.26-7.40 (4H, m), 8.07 (1H, s), 8.18(2H, m), 8.31 (1H, d, J=8.8 Hz), 10.77 (1H, s).

Example 103N1-Methyl-3-chloro-5-(2-((4-(pyrrolidin-1-yl)piperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

A mixture ofN1-methyl-5-(2-amino-4-pyridyl)oxy-3-chloro-1H-1-indolecarboxamide (278mg, Production example 102-1), triethylamine (0.37 ml), tetrahydrofuran(5 ml) was ice-cooled and stirred; phenyl chloroformate (0.33 ml) wasadded dropwise to the mixture; and the reaction mixture was furtherstirred for 10 minutes. Water was added thereto; extraction wasperformed with ethyl acetate; and purification by silica gel columnchromatography was performed to yield a 373 mg of residue. A portion of245 mg of the residue was dissolved in N,N-dimethylformamide (2 ml);4-(1-pyrrolidinyl)piperidine (345 mg) was added thereto; and thereaction mixture was stirred at room temperature for 30 minutes.Extraction was performed with ethyl acetate after the addition of water;and the organic layer was washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (Fuji SilysiaNH) to yield the title compound (154 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.19-1.30 (2H, m), 1.58-1.68 (4H, m),1.70-1.78 (2H, m), 2.03-2.13 (1H, m), 2.36-2.46 (4H, m), 2.77-2.87 (5H,m), 3.88-3.97 (2H, m), 6.55 (1H, d, J=5.6 Hz), 7.16 (1H, dd. J=9.2, 2.4Hz), 7.27 (1H, d, J=2.4 Hz), 7.32 (1H, s), 8.08 (1H, d, J=5.6 Hz), 8.10(1H, s), 8.19-8.22 (1H, m), 8.33 (1H, d, J=9.2 Hz), 9.13 (1H, brs).

Example 104N1-Methyl-3-chloro-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

A mixture ofN1-methyl-5-(2-amino-4-pyridyl)oxy-3-chloro-1H-1-indolecarboxamide (480mg, Production example 102-1), triethylamine (0.63 ml), tetrahydrofuran(15 ml) was ice-cooled and stirred; phenyl chloroformate (710 mg) wasadded dropwise to the mixture; and the reaction mixture was furtherstirred for 10 minutes. Extraction was performed with ethyl acetateafter addition of water; and purification was performed by silica gelcolumn chromatography (hexane:ethyl acetate=1:1). The obtained residuewas dissolved in N,N-dimethylformamide (5 ml); 4-hydroxypiperidine (450mg) was added thereto; and the reaction mixture was stirred at roomtemperature overnight. Water was added to the reaction mixture;extraction was performed with ethyl acetate; and purification wasperformed by silica gel column chromatography (Fuji Silysia NH, ethylacetate:methanol=40:1) to yield the title compound as colorless powder(78 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.30 (2H, m), 1.61-1.79 (2H, m),2.82 (3H, d, J=4.4 Hz), 2.94-3.03 (2H, m), 3.56-3 63 (1H, m), 3.70-3.78(2H, m), 4.64 (1H, d, J=4.0 Hz), 6.55 (1H, dd, J=5.6, 2.4 Hz), 7.16 (1H,dd, J=8.8, 2.4 Hz), 7.27 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=2.4 Hz), 8.08(1H, d, J=5.6 Hz), 8.09 (1H, s), 8.21 (1H, q, J=4.4 Hz), 8.32 (1H, d,J=8.8 Hz), 9.13 (1H, s).

Example 105N1-Methyl-3-chloro-5-(2-(((3-(4-hydroxypiperidino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 103, the title compound was obtained as whitecrystals from 1-(3-aminopropyl)-4-hydroxypiperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.25-1.38 (2H, m), 1.48-1.58 (2H, m),1.62-1.70 (2H, m), 1.86-1.97 (2H, m), 2.18-2.25 (2H, m), 2.60-2.68 (2H,m), 2.83 (3H, d, J=3.6 Hz), 3.02-3.13 (2H, m), 3.34-3.42 (1H, m), 4.49(1H, d, J=4.0 Hz), 6.52 (1H, dd, J=6.0, 2.4 Hz), 6.84-6.86 (1H, m), 7.17(1H, dd, J=8.8, 2.4 Hz), 7.28 (1H, d, J=2.4 Hz), 8.01-8.05 (2H, m), 8.10(1H, s), 8.19-8.24 (1H, m), 8.33 (1H, d, J=8.8 Hz), 9.04 (1H, brs).

The starting materials were synthesized as follows.

Production Example 105-12-(3-(4-Hydroxypiperidino)propyl)isoindolin-1,3-dione

N-(3-bromopropyl)phthalimide (26.8 g), 4-hydroxypiperidine (15.0 g) andpotassium carbonate (27.6 g) were added to N,N-dimethylformamide; andthe reaction mixture was stirred at room temperature overnight. Afterthe addition of water, extraction was performed with ethyl acetate; theorganic layer was washed with water and brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure to yield thetitle compound (13.9 g).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-2.05 (6H, m), 2.10-2.60 (4H, m),2.70-2.90 (2H, m), 3.60-3.85 (3H, m), 7.70-7.75 (2H, m), 7.82-7.87 (2H,m).

Production Example 105-2 BenzylN-(3-(4-hydroxypiperidino)propyl)carbamate

Ethanol (100 ml) and hydrazine hydrate (1.5 g) were added to2-(3-(4-hydroxypiperidino)propyl)isoindolin-1,3-dione (4.5 g); thereaction mixture was heated to reflux for 2.5 hours; and the producedcrystals were filtered off. N-Methylmorpholine (2.5 ml) andN-(benzyloxycarbonyloxy)succinimide (5.2 g) were added to the filtrate;and the reaction mixture was stirred at room temperature overnight.Aqueous solution of sodium hydrogencarbonate was added to the reactionmixture; extraction was performed with ethyl acetate; and the organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to yield the title compound(2.96 g).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.52-2.10 (6H, m), 2.10-2.60 (4H, m),2.78-2.90 (2H, m), 3.24-3.33 (2H, m), 3.53-3.86 (1H, m), 5.09 (2H, s),5.88-5.96 (1H, m), 7.28-7.38 (5H, m).

Production Example 105-3 1-(3-Aminopropyl)-4-hydroxypiperidine

Ethanol (200 ml) and palladium carbon (2.5 g) were added to benzylN-(3-(4-hydroxypiperidino)propyl)carbamate (2.96 g); and the reactionmixture was stirred vigorously under hydrogen atmosphere overnight.Palladium carbon was removed by filtration, and the filtrate wasconcentrated to yield the title compound (1.5 g).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.25-1.38 (2H, m), 1.41-1.49 (2H, m),1.61-1.69 (2H, m), 1.84-1.95 (2H, m), 2.18-2.25 (2H, m), 2.49-2.57 (2H,m), 2.58-2.69 (2H, m), 3.30-3.42 (1H, m).

Example 106N1-Methyl-3-chloro-5-(2-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 104, the title compound was obtained from4-(2-hydroxyethyl)piperazine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.30-2.48 (6H, m), 2.82 (3H, d, J=4.4Hz), 3.30-3.40 (4H, m), 3.46 (2H, q, J=5.6 Hz), 4.38 (1H, t, J=5.6 Hz),6.57 (1H, dd, J=5.6, 2.4 Hz), 7.16 (1H, dd, J=8.8, 2.4 Hz), 7.29 (1H, d,J=2.4 Hz), 7.32 (1H, d, J=2.4 Hz), 8.07-8.13 (2H, m), 8.21 (1H, q, J=4.4Hz), 8.32 (1H, d, J=8.8 Hz), 9.15 (1H, s).

Example 107N4-(4-(3-Chloro-1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide

Similarly to Example 104, the title compound was obtained frommorpholine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.82 (3H, d, J=4.4 Hz), 3.33-3.40(4H, m), 3.49-3.56 (4H, m), 6.58 (1H, dd, J=5.6, 2.4 Hz), 7.16 (1H, dd,J=8.8, 2.4 Hz), 7.27 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=2.4 Hz),8.06-8.13 (2H, m), 8.21 (1H, q, J=4.4 Hz), 8.32 (1H, d, J=8.8 Hz), 9.22(1H, s).

Example 108N1-Methyl-3-chloro-5-(2-((4-ethylpiperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 103, the title compound was obtained fromN-ethylpiperazine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.96 (3H, t, J=7.2 Hz), 2.24-2.32(6H, m), 2.82 (3H, d, J=4.0 Hz), 3.34-3.39 (4H, m), 6.57 (1H, dd, J=6.0,2.4 Hz), 7.17 (1H, dd, J=9.2, 2.4 Hz), 7.27 (1H, d, J=2.4 Hz), 7.32 (1H,d, J=2.4 Hz), 8.07-8.10 (2H, m), 8.18-8.25 (1H, m), 8.33 (1H, d, J=9.2Hz), 9.17 (1H, brs).

Example 109N1-Ethyl-3-chloro-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 104, the title compound was obtained as a colorlessamorphous solid fromN1-ethyl-5-(2-amino-4-pyridyl)oxy-3-chloro-1H-1-indolecarboxamide.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.15 (2H, m), 1.61 (3H, t, J=7.2 Hz),1.60-1.70 (2H, m), 2.94-3.02 (2H, m), 3.26-3.36 (2H, m), 3.56-3.63 (1H,m), 3.70-3.78 (2H, m), 4.64 (1H, d, J=4.4 Hz), 6.55 (1H, dd, J=5.6, 2.4Hz), 7.16 (1H, dd, J=8.8, 2.4 Hz), 7.27 (1H, d, J=2.4 Hz), 7.32 (1H, d,J=2.4 Hz), 8.08 (1H, d, J=5.6 Hz), 8.13 (1H, s), 8.22-8.27 (1H, m), 8.32(1H, d, J=8.8 Hz), 9.12 (1H, s).

The starting material was synthesized as follows.

Production Example 109-1N1-Ethyl-5-(2-amino-4-pyridyl)oxy-3-chloro-1H-1-indolecarboxamide

Phenyl N-ethylcarbamate was added to a solution of5-(2-amino-4-pyridyl)oxy-3-chloro-1H-1-indole (1.35 g, CAS No.417721-98-3) which was described in WO 02/32872, sodium hydride (210 mg)and N,N-dimethylformamide; and the reaction mixture was stirred for 1hour. An aqueous solution of ammonium chloride was added to the reactionmixture; extraction was performed with ethyl acetate; and purificationby silica gel column chromatography (Fuji Silysia NH, hexane:ethylacetate=1:2) to yield the title compound as a colorless oil (1.07 g).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.15 (3H, t, J=7.2 Hz), 3.25-3.35(2H, m), 5.76 (1H, d, J=2.4 Hz), 5.87 (2H, s), 6.14 (1H, dd, J=5.6, 2.4Hz), 7.13 (1H, dd, J=8.8, 2.4 Hz), 7.23 (1H, d, J=2.4 Hz), 7.77 (1H, d,J=5.6 Hz), 8.11 (1H, s), 8.20-8.25 (1H, m), 8.31 (1H, d, J=8.8 Hz).

Example 110N1-Ethyl-3-chloro-5-(2-(((3-(4-hydroxypiperidino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 103, the title compound was obtained as whitecrystals fromN1-ethyl-5-(2-amino-4-pyridyl)oxy-3-chloro-1H-1-indolecarboxamide and1-(3-aminopropyl)-4-hydroxypiperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.16 (3H, t, J=7.2 Hz), 1.26-1.38(2H, m), 1.48-1.57 (2H, m), 1.63-1.70 (2H, m), 1.86-1.97 (2H, m),2.18-2.25 (2H, m), 2.60-2.68 (2H, m), 3.05-3.13 (2H, m), 3.26-3.34 (2H,m), 3.34-3.42 (1H, m), 4.49 (1H, d, J=4.0 Hz), 6.52 (1H, dd, J=6.0, 2.4Hz), 6.84-6.86 (1H, m), 7.16 (1H, dd, J=8.8, 2.4 Hz), 7.28 (1H, d, J=2.4Hz), 7.98-8.05 (2H, m), 8.14 (1H, s), 8.22-8.28 (1H, m), 8.33 (1H, d,J=8.8 Hz), 9.03 (1H, brs).

Example 111N1-Ethyl-3-chloro-5-(2-(((3-(diethylamino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 104, the title compound was obtained fromN1-ethyl-5-(2-amino-4-pyridyl)oxy-3-chloro-1H-1-indolecarboxamide and3-(diethylamino)propylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.90 (6H, t, J=7.2 Hz), 1.16 (3H, t,J=7.2 Hz), 1.46-1.54 (2H, m), 2.33-2.44 (6H, m), 3.07-3.14 (2H, m),3.26-3.34 (2H, m), 6.52 (1H, dd, J=5.6, 2.4 Hz), 6.83 (1H, s), 7.16 (1H,dd, J=8.8, 2.4 Hz), 7.28 (1H, d, J=2.4 Hz), 8.02 (1H, d, J=5.6 Hz),8.04-8.13 (1H, brs), 8.14 (1H, s), 8.23-8.27 (1H, m), 8.33 (1H, d, J=8.8Hz), 9.04 (1H, s).

Example 112N1,3-Dimethyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 104, the title compound was obtained as a colorlessamorphous solid fromN1,3-dimethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17-1.30 (2H, m), 1.61-1.70 (2H, m),2.19 (3H, s), 2.80 (3H, d, J=4.0 Hz), 2.94-3.03 (2H, m), 3.56-3.64 (1H,m), 3.70-3.78 (2H, m), 4.64 (1H, d, J=4.0 Hz), 6.52 (1H, dd, J=5.6, 2.4Hz), 7.02 (1H, dd, J=8.8, 2.4 Hz), 7.29-7.33 (2H, m), 7.66 (1H, s), 8.00(1H, q, J=4.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.25 (1H, d, J=8.8 Hz), 9.08(1H, s).

The starting materials were synthesized as follows.

Production Example 112-1 4-(3-Methyl-1H-5-indolyl)oxy-2-pyridinamine

A mixture of 5-hydroxy-3-methylindole (4.7 g), 2-amino-4-chloropyridine(4.1 g), sodium hydride (1.3 g), and dimethyl sulfoxide (40 ml) wasstirred at 160° C. for 15 hours. Water was added thereto; extraction wasperformed with ethyl acetate; and purification was performed by silicagel column chromatography (ethyl acetate, sequentially, ethylacetate:methanol=20:1). The solvent was distilled off to yield the titlecompound as a brown solid (1.6 g).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.29 (3H, s), 5.70 (1H, d, J=2.4 Hz),5.77 (2H, s), 6.10 (1H, dd, J=5.6, 2.4 Hz), 6.80 (1H, dd, J=8.8, 2.4Hz), 7.15 (1H, s), 7.17 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=8.8 Hz), 7.72(1H, d, J=5.6 Hz), 10.83 (1H, s).

Production Example 112-2N1,3-Dimethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Phenyl N-methylcarbamate (350 mg, Production example 2-1) was added to asolution of 4-(3-methyl-1H-5-indolyl)oxy-2-pyridinamine (500 mg), sodiumhydride (93 mg) and N,N-dimethylformamide (5 ml) at room temperature;and the reaction mixture was stirred for 2 hours and 45 minutes. Waterwas added to the reaction mixture; extraction was performed with ethylacetate; and purification was performed by NH-silica gel columnchromatography (Fuji Silysia, hexane:ethyl acetate=1:2, sequentially,ethyl acetate) to yield the title compound as a pale yellow amorphoussolid (365 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.19 (3H, s), 2.80 (3H, d, J=4.0 Hz),5.73 (1H, d, J=2.4 Hz), 5.83 (2H, s), 6.12 (1H, dd, J=5.6, 2.4 Hz), 7.00(1H, dd, J=8.8, 2.4 Hz), 7.27 (1H, d, J=2.4 Hz), 7.64 (1H, s), 7.75 (1H,d, J=5.6 Hz), 7.98 (1H, q, J=4.0 Hz), 8.24 (1H, d, J=8.8 Hz).

Example 113N1,3-Dimethyl-5-(2-((4-(pyrrolidin-1-yl)piperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 104, the title compound was obtained as a colorlessamorphous solid fromN1,3-dimethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide and4-(1-pyrrolidinyl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17-1.79 (2H, m), 1.60-1.67 (4H, m),1.70-1.79 (2H, m), 2.03-2.13 (1H, m), 2.19 (3H, s), 2.40-2.57 (4H, m),2.77-2.86 (5H, m), 3.88-3.96 (2H, m), 6.52 (1H, dd, J=5.6, 2.4 Hz), 7.02(1H, dd, J=8.8, 2.4 Hz), 7.28-7.85 (2H, m), 7.66 (1H, s), 8.00 (1H, q,J=4.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.25 (1H, d, J=8.8 Hz), 9.08 (1H, s).

Example 114N1-Cyclopropyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-3-methyl-1H-1-indolecarboxamide

Similarly to Example 104, the title compound was obtained as a colorlessamorphous solid fromN1-cyclopropyl-5-(2-amino-4-pyridyl)oxy-3-methyl-1H-1-indolecarboxamide.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.56-0.60 (2H, m), 2.67-2.73 (2H, m),1.19-1.29 (2H, m), 1.61-1.70 (2H, m), 2.18 (3H, s), 2.72-2.78 (1H, m),2.94-3.03 (2H, m), 3.56-3.63 (1H, m), 3.70-3.77 (2H, m), 4.64 (1H, d,J=4.0 Hz), 6.51 (1H, dd, J=5.6, 2.4 Hz), 7.02 (1H, dd, J=8.8, 2.4 Hz),7.28-7.32 (2H, m), 7.65 (1H, s), 8.05 (1H, d, J=5.6 Hz), 8.11 (1H, d,J=2.4 Hz), 8.24 (1H, d, J=8.8 Hz), 9.08 (1H, s).

The starting material was synthesized as follows.

Production Example 114-1N1-Cyclopropyl-5-(2-amino-4-pyridyl)oxy-3-methyl-1H-1-indolecarboxamide

Similarly to Production example 112-2, the title compound was obtainedas a colorless amorphous solid from phenyl N-cyclopropylcarbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.55-0.60 (2H, m), 0.68-0.73 (2H, m),2.18 (3H, s), 2.70-2.79 (1H, m), 5.73 (1H, d, J=2.4 Hz), 5.83 (2H, s),6.12 (1H, dd, J=5.6, 2.4 Hz), 7.00 (1H, dd, J=8.8, 2.4 Hz), 7.26 (1H, d,J=2.4 Hz), 7.63 (1H, s), 7.75 (1H, d, J=5.6 Hz), 8.09 (1H, d, J=2.4 Hz),8.23 (1H, d, J=8.8 Hz).

Example 115N1-Cyclopropyl-5-(2-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-3-methyl-1H-1-indolecarboxamide

Similarly to Example 104, the title compound was obtained as a colorlessamorphous solid fromN1-cyclopropyl-5-(2-amino-4-pyridyl)oxy-3-methyl-1H-1-indolecarboxamideand 1-(2-hydroxyethyl)piperazine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.57-0.60 (2H, m), 0.67-0.74 (2H, m),2.18 (3H, s), 2.30-2.37 (6H, m), 2.70-2.78 (1H, m), 3.30-3.38 (4H, m),3.46 (2H, q, J=6.4 Hz), 4.38 (1H, t, J=6.4 Hz), 6.53 (1H, dd, J=5.6, 2.4Hz), 7.02 (1H, dd, J=8.8, 2.4 Hz), 7.28-7.32 (2H, m), 7.65 (1H, s), 8.06(1H, d, J=5.6 Hz), 8.11 (1H, d, J=2.4 Hz), 8.24 (1H, d, J=8.8 Hz), 9.10(1H, s).

Example 116N1-Methyl-5-(2-((methylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound was obtained as whitecrystals (19.5 mg, 0.058 mmol, 58%) from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 and 40%methylamine in methanol.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.64 (3H, d, J=4.4 Hz), 2.83 (3H, d,J=4.4 Hz), 6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.82(1H, d, J=2.4 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz),7.87 (1H, d, J=3.6 Hz), 7.95 (1H, m), 8.02 (1H, d, J=5.6 Hz), 8.16 (1H,m), 8.28 (1H, d, J=8.8 Hz), 9.07 (1H, s).

Example 117N1-Methyl-5-(2-((ethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound was obtained as whitecrystals (15.0 mg, 0.042 mmol, 42%) from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 and 2.0 Methylamine in tetrahydrofuran.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.02 (3H, t, J=7.2 Hz), 2.83 (3H, d,J=4.0 Hz), 3.10 (2H, m), 6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d,J=3.6 Hz), 6.86 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36(1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 7.96 (1H, m), 8.02 (1H, d,J=5.6 Hz), 8.17 (1H, m), 8.28 (1H, d, J=8.8 Hz), 8.99 (1H, s).

Example 118N1-Methyl-5-(2-((cyclopropylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound was obtained as whitecrystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 andcyclopropylamine.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 0.58-0.62 (2H, m), 0.71-0.79 (2H, m),2.70 (1H, m), 3.07 (3H, d, J=4.8 Hz), 5.64 (1H, m), 6.26 (1H, m), 6.41(1H, m), 6.58 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.20-7.30(2H, m), 7.42-7.53 (2H, m), 7.90 (1H, d, J=5.6 Hz), 8.19 (1H, d, J=8.8Hz).

Example 119N1-Methyl-5-(2-((diethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound was obtained as whitecrystals (24.7 mg, 0.065 mmol, 65%) from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 anddiethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.01 (6H, t, J=7.2 Hz), 2.82 (3H, d,J=4.4 Hz), 3.20-3.50 (4H, m), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d,J=3.6 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.40(1H, d, J=2.4 Hz), 7.78 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.6 Hz), 8.16(1H, m), 8.28 (1H, d, J=8.8 Hz), 8.59 (1H, s).

Example 120N1-Methyl-5-(2-((1-propylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (28.0 mg, 0.076 mmol, 76%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 and1-propylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.83 (3H, t, J=7.2 Hz), 1.40 (2H, m),2.83 (3H, d, J=4.4 Hz), 3.04 (2H, m), 6.49 (1H, dd, J=2.4, 5.6 Hz), 6.67(1H, d, J=3.6 Hz), 6.86 (1H, s), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H,d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.01-8.03 (2H, m), 8.16 (1H, m),8.28 (1H, d, J=8.8 Hz), 9.00 (1H, s).

Example 121N1-Methyl-5-(2-((2-propylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (20.7 mg, 0.056 mmol, 56%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 and2-propylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (6H, d, J=6.8 Hz), 2.83 (3H, d,J=4.4 Hz), 3.74 (1H, m), 6.49 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d,J=3.6 Hz), 6.89 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36(1H, d, J=2.4 Hz), 7.81 (1H, m), 7.87 (1H, d, J=3.6 Hz), 8.02 (1H, d,J=5.6 Hz), 8.16 (1H, m), 8.28 (1H, d, J=8.8 Hz), 8.90 (1H, s).

Example 122N1-Methyl-5-(2-((cyclopentylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (30.7 mg, 0.078 mmol, 78%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 andcyclopentylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.10-1.90 (8H, m), 2.83 (3H, d, J=4.4Hz), 3.89 (1H, m), 6.50 (1H, d, J=2.4, 5.6 Hz), 6.68 (1H, d, J=3.6 Hz),6.90 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4Hz), 7.87 (1H, m), 7.93 (1H, d, J=3.6 Hz), 8.00 (1H, d, J=5.6 Hz), 8.15(1H, m), 8.28 (1H, d, J=8.8 Hz), 8.89 (1H, s).

Example 123N1-Methyl-5-(2-((cyclohexylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (32.5 mg, 0.080 mmol, 80%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 and cyclohexylamine.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.00-2.00 (8H, m), 2.83 (3H, d, J=4.4Hz), 3.40-3.60 (2H, m), 3.75 (1H, m), 6.11 (1H, s), 6.43 (1H, m), 6.60(1H, d, J=3.6 Hz), 6.95 (1H, m), 7.04 (1H, m), 7.20-7.30 (2H, m), 7.44(1H, d, J=3.6 Hz), 7.95 (1H, d, J=5.6 Hz), 8.20 (1H, d, J=8.8 Hz), 9.20(1H, m).

Example 124N1-Methyl-5-(2-((2-propenylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (18.5 mg, 0.051 mmol, 51%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 and allylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.8 Hz), 3.75 (2H, m),5.06 (1H, dd, J=1.6, 10.4 Hz), 5.14 (1H, dd, J=1.6, 17.2 Hz), 5.87 (1H,m), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.69 (1H, d, J=3.6 Hz), 6.87 (1H, d,J=2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.39 (1H, d, J=2.4 Hz), 7.89(1H, d, J=3.6 Hz), 8.05 (1H, d, J=5.6 Hz), 8.16-8.19 (2H, m), 8.30 (1H,d, J=8.8 Hz), 9.13 (1H, s).

Example 125N1-Methyl-5-(2-((2-propynylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (16.8 mg, 0.046 mmol, 46%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 andpropargylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.4 Hz), 3.12(1H, m),3.92 (2H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.70 (1H, d, J=3.6 Hz), 6.87(1H, d, J=2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.39 (1H, d, J=2.4 Hz),7.89 (1H, d, J=3.6 Hz), 8.07 (1H, d, J=5.6 Hz), 8.18 (1H, m), 8.29-8.31(2H, m), 9.21 (1H, s).

Example 126N1-Methyl-5-(2-((benzylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (26.1 mg, 0.063 mmol, 63%)was obtained as white crystals from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 and benzylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.4 Hz), 4.34 (2H, d,J=5.6 Hz), 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.69 (1H, d, J=3.6 Hz), 6.90(1H, d, J=2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.20-7.35 (5H, m), 7.39(1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 8.04 (1H, d, J=5.6 Hz), 8.17(1H, m), 8.30 (1H, d, J=8.8 Hz), 8.51 (1H, m), 9.17 (1H, s).

Example 127N1-Methyl-5-(2-((furfurylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (9.1 mg, 0.022 mmol, 22%) wasobtained as white powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 andfurfurylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.4 Hz), 4.32 (2H, d,J=5.2 Hz), 6.24 (1H, s), 6.38 (1H, s), 6.54 (1H, m), 6.69 (1H, d, J=3.6Hz), 6.90 (1H, s), 7.06 (1H, m), 7.39 (1H, s), 7.57 (1H, s), 7.89 (1H,d, J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz), 8.18 (1H, m), 8.31 (1H, d, J=8.8Hz), 8.38 (1H, m), 9.15 (1H, s).

Example 128N1-Methyl-5-(2-((thiophen-2-ylmethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 5, the title compound (22.6 mg, 0.054 mmol, 54%)was obtained as white powder from phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(52 mg, 0.1 mmol) synthesized in Production example 5-2 and2-thiophenemethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.4 Hz), 4.50 (2H, d,J=5.6 Hz), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.69 (1H, d, J=3.6 Hz),6.88-6.98 (3H, m), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.35-7.39 (2H, m), 7.89(1H, d, J=3.6 Hz), 8.04 (1H, d, J=5.6 Hz), 8.18 (1H, m), 8.30 (1H, d,J=8.8 Hz), 8.55 (1H, m), 9.18 (1H, s).

Example 129N1-Ethyl-5-(2-((ethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (23.1 mg, 0.063 mmol, 63%)was obtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (42mg, 0.1 mmol) synthesized in Production example 27-2 and 2.0 Methylamine in tetrahydrofuran.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.04 (3H, t, J=7.2 Hz), 1.18 (3H, t,J=7.2 Hz), 3.12 (2H, m), 3.31 (2H, m), 6.52 (1H, dd, J=2.4, 5.6 Hz),6.69 (1H, d, J=3.6 Hz), 6.88 (1H, d, J=2.4 Hz), 7.05 (1H, dd, J=2.4, 8.8Hz), 7.38 (1H, d, J=2.4 Hz), 7.92 (1H, d, J=3.6 Hz), 7.97 (1H, m), 8.04(1H, d, J=5.6 Hz), 8.23 (1H, m), 8.30 (1H, d, J=8.8 Hz), 9.01 (1H, s).

Example 130N1-Ethyl-5-(2-((diethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 27, the title compound (25.8 mg, 0.065 mmol, 65%)was obtained as white crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (42mg, 0.1 mmol) synthesized in Production example 27-2 and diethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.03 (6H, t, J=7.2 Hz), 1.19 (3H, t,J=7.2 Hz), 3.20-3.40 (6H, m), 6.55 (1H, dd, J=2.4, 5.6 Hz), 6.69 (1H, d,J=3.6 Hz), 7.05 (1H, dd, J=2.4, 8.8 Hz), 7.38 (1H, s), 7.43 (1H, d,J=2.4 Hz), 7.92 (1H, d, J=3.6 Hz), 8.08 (1H, d, J=5.6 Hz), 8.23 (1H, m),8.30 (1H, d, J=8.8 Hz), 8.62 (1H, s).

Example 131N1-Dimethyl-5-(2-((methylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (17.5 mg, 0.05 mmol, 35%)was obtained as white powder fromN1-dimethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (42 mg, 0.14mmol) and 40% methylamine in methanol.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.67 (3H, d, J=4.4 Hz), 3.05 (6H, s),6.53 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.83 (1H, d, J=2.4Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.40 (1H, d, J=2.4 Hz), 7.68-7.71(2H, m), 8.00-8.05 (2H, m), 9.10 (1H, s).

The starting materials were synthesized by the following methods.

Production Example 131-1 Phenyl N,N-dimethylcarbamate

Similarly to Production example 2-1, the title compound (6.27 g, 0.038mol, 38%) was obtained as a colorless oil from 2.0 M diethylamine intetrahydrofuran (50 ml, 0.1 mol), phenyl chloroformate (13.8 ml, 0.11mol) and pyridine (8.9 ml, 0.11 mol).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.02 (3H, s), 3.11 (3H, s), 7.09-7.39(5H, m).

Production Example 131-2N1-Dimethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Production example 1-3, the title compound (128 mg, 0.43mmol, 43%) was obtained as white crystals from4-(1H-5-indolyloxy)-2-pyridinamine (225 mg, 1.0 mmol) and phenylN,N-dimethylcarbamate.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.13 (6H, s), 4.36 (2H, brs), 5.92 (1H,d, J=2.4 Hz), 6.31 (1H, dd, J=2.4, 5.6 Hz), 6.59 (1H, d, J=3.6 Hz), 7.03(1H, dd, J=2.4, 8.8 Hz), 7.30 (1H, d, J=2.4 Hz), 7.37 (1H, d, J=3.6 Hz),7.70 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=5.6 Hz).

Example 132N1-Dimethyl-5-(2-((ethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (21.4 mg, 0.058 mmol, 41%)was obtained as white powder fromN1-dimethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (42 mg, 0.14mmol) and 2.0 M ethylamine in tetrahydrofuran.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.05 (3H, t, J=7.2 Hz), 3.05 (6H, s),3.13 (2H, m), 6.52 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.87(1H, d, J=2.4 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.40 (1H, d, J=2.4 Hz),7.68-7.71 (2H, m), 8.00-8.05 (2H, m), 9.02 (1H, s).

Example 133N1-Dimethyl-5-(2-((dimethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (15.1 mg, 0.041 mmol, 29%)was obtained as white powder fromN1-dimethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (42 mg, 0.14mmol) and 2.0 M dimethylamine in tetrahydrofuran.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (6H, s), 3.03 (6H, s), 6.54 (1H,d, J=5.6 Hz), 6.65 (1H, d, J=3.6 Hz), 7.02 (1H, d, J=8.8 Hz), 7.30-7.50(2H, m), 7.60-7.69 (2H, m), 8.06 (1H, d, J=5.6 Hz), 8.81 (1H, s).

Example 134N1-Benzyl-5-(2-((methylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (12.5 mg, 0.030 mmol, 24%)was obtained as white powder fromN1-benzyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (45 mg, 0.13mmol) and 40% methylamine in methanol.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.66 (3H, d, J=4.4 Hz), 4.51 (2H, d,J=5.6 Hz), 6.52 (1H, dd, J=2.4, 5.6 Hz), 6.72 (1H, d, J=3.6 Hz), 6.84(1H, d, J=2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.20-7.44 (6H, m), 7.96(1H, m), 8.00-8.05 (2H, m), 8.31 (1H, d, J=8.8 Hz), 8.83 (1H, t, J=5.6Hz), 9.09 (1H, s).

The starting material was synthesized by the following methods.

Production Example 134-1N1-Benzyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Production example 1-3, the title compound (45 mg, 0.13mmol, 13%) was obtained as white powder from4-(1H-5-indolyloxy)-2-pyridinamine (225 mg, 1.0 mmol) and phenylN-benzylcarbamate.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.38 (2H, brs), 4.68 (2H, d, J=4.0 Hz),5.82 (1H, m), 5.92 (1H, m), 6.30 (1H, m), 6.61 (1H, d, J=3.6 Hz), 7.07(1H, dd, J=2.4, 8.8 Hz), 7.26-7.47 (7H, m), 7.91 (1H, d, J=5.6 Hz), 8.19(1H, d, J=8.8 Hz).

Example 1355-(2-((Methylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indole-1-carboxylicacid pyrrolidin-1-ylamide

Similarly to Example 28, the title compound (21.1 mg, 0.056 mmol, 27%)was obtained as white powder from5-(2-amino-4-pyridyl)oxy-1H-1-indole-1-carboxylic acidpyrrolidin-1-ylamide (67 mg, 0.21 mmol) and 40% methylamine in methanol.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.80-2.00 (4H, m), 2.67 (3H, d, J=4.4Hz), 3.40-3.60 (4H, m), 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.66 (1H, d, J=3.6Hz), 6.85 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.39 (1H, d,J=2.4 Hz), 7.80 (1H, d, J=3.6 Hz), 7.83 (1H, d, J=8.8 Hz), 8.00 (1H, m),8.04 (1H, d, J=5.6 Hz), 9.10 (1H, s).

The starting materials were synthesized by the following methods.

Production Example 135-1 Phenyl pyrrolidin-1-ylcarboxylate

Similarly to Production example 2-1, the title compound (2.68 g, 0.014mol, 14%) was obtained as white crystals from pyrrolidine (8.3 ml, 0.1mol), phenyl chloroformate (13.8 ml, 0.11 mol) and pyridine (8.9 ml,0.11 mol).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.90-1.99 (4H, m), 3.46-3.59 (4H, m),7.20-7.37 (5H, m).

Production Example 135-25-(2-Amino-4-pyridyl)oxy-1H-1-indole-1-carboxylic acidpyrrolidin-1-ylamide

Similarly to Production example 1-3, the title compound (146 mg, 0.45mmol, 60%) was obtained as white powder from4-(1H-5-indolyloxy)-2-pyridinamine (170 mg, 0.76 mmol) and phenylpyrrolidin-1-ylcarboxylate.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.96-2.02 (4H, m), 3.60-3.67 (4H, m),4.35 (2H, brs), 5.91 (1H, d, J=2.4 Hz), 6.31 (1H, dd, J=2.4, 5.6 Hz),6.57 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.29 (1H, d, J=2.4Hz), 7.43 (1H, d, J=3.6 Hz), 7.88 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=5.6Hz).

Example 1365-(2-((Pyrrolidin-1-ylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indole-1-carboxylicacid pyrrolidin-1-ylamide

Similarly to Example 28, the title compound (6.2 mg, 0.015 mmol, 9.2%)was obtained as white powder from5-(2-amino-4-pyridyl)oxy-1H-1-indole-1-carboxylic acidpyrrolidin-1-ylamide (52 mg, 0.16 mmol) and pyrrolidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.70-1.90 (8H, m), 3.20-3.40 (4H, m),3.50-3.70 (4H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.66 (1H, d, J=3.6 Hz),7.03 (1H, dd, J=2.4, 8.8 Hz), 7.38 (1H, d, J=2.4 Hz), 7.45 (1H, d, J=2.4Hz), 7.80 (1H, d, J=3.6 Hz), 7.84 (1H, d, J=8.8 Hz), 8.08 (1H, d, J=5.6Hz), 8.61 (1H, s).

Example 137N1-(2-Propynyl)-5-(2-((ethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (16.5 mg, 0.044 mmol, 25%)was obtained as white crystals fromN1-(2-propynyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (54 mg,0.18 mmol) and 2.0 M ethylamine in tetrahydrofuran.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.04 (3H, t, J=7.2 Hz), 3.12 (2H, m),3.23 (1H, m), 4.10 (2H, m), 6.52 (1H, dd, J=2.4, 5.6 Hz), 6.53 (1H, d,J=3.6 Hz), 6.88 (1H, d, J=2.4 Hz), 7.08 (1H, dd, J=2.4, 8.8 Hz), 7.40(1H, d, J=2.4 Hz), 7.92 (1H, d, J=3.6 Hz), 8.00 (1H, m), 8.04 (1H, d,J=5.6 Hz), 8.31 (1H, d, J=8.8 Hz), 8.73 (1H, m), 9.02 (1H, s).

The starting materials were synthesized by the following methods.

Production Example 137-1 Phenyl N-(2-propynyl)carbamate

Similarly to Production example 2-1, the title compound (7.64 g, 0.044mol, 87%) was obtained as white crystals from 2-propynylamine (3.43 ml,0.05 mol), phenyl chloroformate (6.9 ml, 0.055 mol) and pyridine (4.45ml, 0.055 mol).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.30 (1H, t, J=2.8 Hz), 4.05-4.15 (2H,m), 5.22 (1H, brs), 7.10-7.40 (5H, m).

Production Example 137-2N1-(2-Propynyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Production example 1-3, the title compound (169 mg, 0.55mmol, 28%) was obtained as white crystals from4-(1H-5-indolyloxy)-2-pyridinamine (450 mg, 2.0 mmol) and phenylN-(2-propynyl)carbamate.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.35 (1H, m), 4.20-4.40 (4H, m), 5.72(1H, brs), 5.92 (1H, d, J=2.4 Hz), 6.30 (1H, dd, J=2.4, 5.6 Hz), 6.63(1H, d, J=3.6 Hz), 7.08 (1H, dd, J=2.4, 8.8 Hz), 7.30 (1H, d, J=2.4 Hz),7.46 (1H, d, J=3.6 Hz), 7.92 (1H, d, J=5.6 Hz), 8.20 (1H, d, J=8.8 Hz).

Example 138N1-(2-Propynyl)-5-(2-((diethylamino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (27.9 mg, 0.069 mmol, 39%)was obtained as white crystals fromN1-(2-propynyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (54 mg,0.18 mmol) and N,N-diethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.03 (6H, t, J=7.2 Hz), 3.23 (1H, m),3.25-3.40 (4H, m), 4.01 (2H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.72 (1H,d, J=3.6 Hz), 7.08 (1H, dd, J=2.4, 8.8 Hz), 7.39 (1H, d, J=2.4 Hz), 7.43(1H, d, J=2.4 Hz), 7.92 (1H, d, J=3.6 Hz), 8.08 (1H, d, J=5.6 Hz), 8.31(1H, d, J=8.8 Hz), 8.63 (1H, s), 8.73 (1H, m).

Example 139N1-(2-Propynyl)-5-(2-((pyrrolidin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (25.1 mg, 0.062 mmol, 35%)was obtained as white crystals fromN1-(2-propynyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (54 mg,0.18 mmol) and pyrrolidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.70-1.90 (4H, m), 3.22 (1H, m),3.25-3.40 (4H, m), 4.10 (2H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.71 (1H,d, J=3.6 Hz), 7.07 (1H, dd, J=2.4, 8.8 Hz), 7.39 (1H, d, J=2.4 Hz), 7.44(1H, d, J=2.4 Hz), 7.92 (1H, d, J=5.6 Hz), 8.08 (1H, d, J=5.6 Hz), 8.30(1H, d, J=8.8 Hz), 8.62 (1H, s), 8.72 (1H, m).

Example 140N1-Methyl-5-(6-((morpholin-4-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (12.5 mg, 0.032 mmol, 12%)was obtained as pale yellow powder fromN1-methyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (73 mg,0.26 mmol) and morpholine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.83 (3H, d, J=3.6 Hz), 3.43-3.45(4H, m), 3.55-3.58 (4H, m), 6.63 (1H, d, J=3.6 Hz), 7.26 (1H, s), 7.32(1H, d, J=8.8 Hz), 7.77 (1H, d, J=3.6 Hz), 7.90 (1H, s), 8.05 (1H, m),8.14 (1H, d, J=8.8 Hz), 8.29 (1H, s), 9.21 (1H, s), 9.34 (1H, s).

The starting materials were synthesized by the following methods.

Production Example 140-1 6-Chloro-4-(1H-5-indolylamino)pyrimidine

4,6-Dichloropyrimidine (5.89 g, 40 mmol), 5-aminoindole (6.27 g, 47mmol) and N,N-diisopropylethylamine (20.6 ml, 0.12 mol) were dissolvedin N-methylpyrrolidone (80 ml), and the reaction mixture was stirred at50° C. for 2.5 hours. The reaction mixture was partitioned between ethylacetate and water; the aqueous layer was subjected to re-extraction withethyl acetate; and the combined organic layer was washed with brine, anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure; a small amount of ethyl acetate was added to theresidue to crystallize; and the crystals were filtered off, washed withdiethyl ether, and dried under aeration to yield the title compound(3.70 g, 15 mmol, 38%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.42 (1H, m), 6.62 (1H, brs), 7.11(1H, d, J=8.0 Hz), 7.35-7.40 (2H, m), 7.72 (1H, brs), 8.38 (1H, s), 9.68(1H, s), 11.11 (1H, s).

Production Example 140-2 6-Amino-4-(1H-5-indolylamino)pyrimidine

A 7N ammonia in methanol (60 ml) was added to6-chloro-4-(1H-5-indolylamino)pyrimidine (2.455 g, 10 mmol); and thereaction mixture was heated in a sealed tube at 130° C. for 90 hours.The solvent was distilled off under reduced pressure; the residue waspurified by silica gel column chromatography (eluent; ethylacetate:tetrahydrofuran=1:1); diethyl ether was added to crystallize;and the crystals were filtered off, washed with diethyl ether, and driedunder aeration to yield the title compound (1.563 g, 6.9 mmol, 69%) aspale brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.50 (2H, brs), 5.66 (1H, m), 6.55 (1H,m), 6.68 (1H, brs), 7.07 (1H, dd, J=2.4, 8.8 Hz), 7.25-7.28 (1H, m),7.40 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=2.4 Hz), 8.19 (1H, s), 8.29 (1H,brs).

Production Example 140-3N1-Methyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (295 mg, 1.05mmol, 52%) was obtained as white crystals from6-amino-4-(1H-5-indolylamino)pyrimidine (450.5 mg, 2.0 mmol) and phenylN-methylcarbamate.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.09 (3H, d, J=4.0 Hz), 4.56 (2H, brs),5.52 (1H, m), 5.73 (1H, m), 6.61 (1H, d, J=3.6 Hz), 6.66 (1H, brs), 7.19(1H, dd, J=2.4, 8.8 Hz), 7.43 (1H, d, J=3.6 Hz), 7.48 (1H, d, J=2.4 Hz),8.13 (1H, d, J=2.4 Hz), 8.21 (1H, s).

Example 141N1-Methyl-5-(6-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (20.6 mg, 0.045 mmol, 17%)was obtained as white crystals fromN1-methyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (73 mg,0.26 mmol) and 4-(pyrrolidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.36 (2H, m), 1.60-1.70 (4H, m),1.70-1.85 (2H, m), 2.40-2.60 (5H, m), 2.83 (3H, d, J=4.4 Hz), 2.85-2.95(2H, m), 3.95-4.05 (2H, m), 6.63 (1H, d, J=3.6 Hz), 7.24 (1H, s), 7.31(1H, dd, J=2.4, 8.8 Hz), 7.77 (1H, d, J=3.6 Hz), 7.90 (1H, s), 8.05 (1H,m), 8.14 (1H, d, J=8.8 Hz), 8.28 (1H, s), 9.14 (1H, s), 9.31 (1H, s).

Example 142N1-Ethyl-5-(6-((ethylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Sodium hydride (69 mg, 1.73 mmol) was suspended in N,N-dimethylformamide(3 ml); 6-amino-4-(1H-5-indolylamino)pyrimidine (311 mg, 1.38 mmol) wasadded thereto at room temperature under nitrogen stream; the reactionmixture was stirred for 30 minutes; phenyl N-ethylcarbamate (286 mg,1.73 mmol) was added thereto; and the reaction mixture was stirredovernight. The reaction mixture was partitioned between a solventmixture of ethyl acetate-tetrahydrofuran (1:1) and a saturated aqueoussolution of sodium hydrogencarbonate; the organic layer was washed withwater and brine, and dried over anhydrous sodium sulfate; the solventwas distilled off; the residue was purified by silica gel columnchromatography (eluent; ethyl acetate:tetrahydrofuran=1:1); elutedfractions were concentrated; ethyl acetate was added to the residue tocrystallize; and the crystals were filtered off, and dried underaeration to yield the title compound (14.3 mg, 0.039 mmol, 2.8%) aswhite crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.07 (3H, t, J=7.2 Hz), 1.18 (3H, t,J=7.2 Hz), 3.11-3.40 (4H, m), 6.64 (1H, d, J=3.6 Hz), 6.87 (1H, s), 7.29(1H, dd, J=2.4, 8.8 Hz), 7.62 (1H, m), 7.80 (1H, d, J=3.6 Hz), 7.86 (1H,s), 8.09-8.17 (2H, m), 8.27 (1H, s), 9.06 (1H, s), 9.35 (1H, s).

Furthermore, the eluted fractions obtained in the above chromatographywere concentrated; the residue was purified again by silica gel columnchromatography (eluent; ethyl acetate:methanol=95:5); eluted fractionswere concentrated; ethyl acetate was added to the residue tocrystallize; and the crystals were filtered off, and dried underaeration to yieldN1-ethyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (210 mg,0.71 mmol, 51%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18 (3H, t, J=7.2 Hz), 3.20-3.40(2H, m), 5.72 (1H, m), 6.24 (2H, brs), 6.61 (1H, d, J=3.6 Hz), 7.21 (1H,dd, J=2.4, 8.8 Hz), 7.76 (1H, s), 7.79 (1H, d, J=3.6 Hz), 8.01 (1H, s),8.07-8.14 (2H, m), 8.74 (1H, s).

Example 143N1-Ethyl-5-(6-((diethylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (24.5 mg, 0.062 mmol, 26%)was obtained as white crystals fromN1-ethyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (70 mg,0.24 mmol) and diethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.07 (6H, t, J=7.2 Hz), 1.18 (3H, t,J=7.2 Hz), 3.20-3.50 (6H, m), 6.63 (1H, d, J=3.6 Hz), 7.31-7.33 (2H, m),7.80 (1H, d, J=3.6 Hz), 7.91 (1H, s), 8.09-8.15 (2H, m), 8.28 (1H, s),8.66 (1H, s), 9.33 (1H, s).

Example 144N1-Ethyl-5-(6-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (43.3 mg, 0.091 mmol, 39%)was obtained as white crystals fromN1-ethyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (70 mg,0.24 mmol) and 4-(pyrrolidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18 (3H, t, J=7.2 Hz), 1.20-1.36(2H, m), 1.60-1.70 (4H, m), 1.70-1.85 (2H, m), 2.40-2.60 (5H, m),2.85-2.95 (2H, m), 3.20-3.50 (2H, m), 3.95-4.05 (2H, m), 6.63 (1H, d,J=3.6 Hz), 7.24 (1H, s), 7.31 (1H, d, J=8.0 Hz), 7.80 (1H, d, J=3.6 Hz),7.90 (1H, s), 8.10-8.15 (2H, m), 8.28 (1H, s), 9.14 (1H, s), 9.31 (1H,s).

Example 145N1-Ethyl-5-(6-((2-(N,N-diethylamino)ethylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (43.0 mg, 0.098 mmol, 42%)was obtained as white crystals fromN1-ethyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (70 mg,0.24 mmol) and 2-(N,N-diethylamino)ethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.96 (6H, t, J=7.2 Hz), 1.18 (3H, t,J=7.2 Hz), 2.30-2.60 (6H, m), 3.10-3.40 (4H, m), 6.64 (1H, d, J=3.6 Hz),6.87 (1H, s), 7.29 (1H, d, J=8.8 Hz), 7.71 (1H, m), 7.80 (1H, d, J=3.6Hz), 7.88 (1H, s), 8.09-8.20 (2H, m), 8.25 (1H, s), 9.21 (1H, s), 9.34(1H, s).

Example 146N1-Phenyl-5-(6-((diethylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (27.5 mg, 0.062 mmol, 27%)was obtained as white crystals fromN1-phenyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (80 mg,0.23 mmol) and diethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (6H, t, J=7.2 Hz), 3.20-3.40(4H, m), 6.74 (1H, d, J=3.6 Hz), 7.13 (1H, dd, J=2.4, 8.8 Hz), 7.33-7.42(4H, m), 7.64-7.67 (2H, m), 7.98-8.03 (2H, m), 8.13 (1H, d, J=8.8 Hz),8.31 (1H, s), 8.69 (1H, s), 9.39 (1H, s), 10.00 (1H, s).

The starting material was synthesized by the following method.

Production Example 146-1N1-Phenyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (160 mg, 0.46mmol, 35%) was obtained as pale brown powder from6-amino-4-(1H-5-indolylamino)pyrimidine (300 mg, 1.33 mmol) and phenylisocyanate.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.61 (2H, brs), 5.76 (1H, m), 6.68 (1H,d, J=3.6 Hz), 6.77 (1H, s), 7.22-7.25 (2H, m), 7.35-7.45 (3H, m),7.50-7.60 (4H, m), 8.16 (1H, d, J=8.8 Hz), 8.22 (1H, s).

Example 147N1-Phenyl-5-(6-((3-(N,N-diethylamino)propylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (56.2 mg, 0.11 mmol, 48%)was obtained as white powder fromN1-phenyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (80 mg,0.23 mmol) and 3-(N,N-diethylamino)propylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.80-1.00 (6H, m), 1.40-1.65 (2H, m),2.20-2.60 (6H, m), 3.00-3.40 (2H, m), 6.70-6.88 (2H, m), 7.10-7.17 (1H,m), 7.30-7.49 (3H, m), 7.60-7.80 (3H, m), 7.90-8.40 (4H, m), 9.10-9.40(2H, m), 10.00-10.14 (1H, m).

Example 148N1-Cyclopropyl-5-(6-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, a crude product ofN1-cyclopropyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide(132 mg) was obtained as white powder from6-amino-4-(1H-5-indolylamino)pyrimidine (300 mg, 1.33 mmol) and phenylN-cyclopropylcarbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.60-0.63 (2H, m), 0.70-0.74 (2H, m),2.76 (1H, m), 5.73 (1H, s), 6.24 (2H, brs), 6.59 (1H, d, J=3.6 Hz), 7.02(1H, dd, J=2.4, 8.8 Hz), 7.74-7.76 (2H, m), 8.01 (1H, s), 8.12 (1H, d,J=8.8 Hz), 8.15 (1H, d, J=2.4 Hz), 8.75 (1H, s).

Similarly to Example 28, the title compound (20.6 mg, 0.041 mmol, 3.1%in 2 processes) was obtained as white crystals from the above crudeproduct.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.59-0.63 (2H, m), 0.70-0.76 (2H, m),1.20-1.60 (8H, m), 1.60-1.80 (2H, m), 2.30-2.80 (8H, m), 4.05-4.20 (2H,m), 6.61 (1H, d, J=3.6 Hz), 7.24 (1H, s), 7.32 (1H, dd, J=2.4, 8.8 Hz),7.76 (1H, d, J=3.6 Hz), 7.90 (1H, s), 8.13 (1H, d, J=8.8 Hz), 8.17 (1H,d, J=2.4 Hz), 8.28 (1H, s), 9.15 (1H, s), 9.32 (1H, s).

Example 149N1-Dimethyl-5-(6-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (19.2 mg, 0.040 mmol, 21%)was obtained as white powder fromN1-dimethyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (56mg, 0.19 mmol) and 4-(pyrrolidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.36 (2H, m), 1.60-1.70 (4H, m),1.70-1.85 (2H, m), 2.40-2.60 (5H, m), 2.85-2.95 (2H, m), 3.00 (6H, s),3.95-4.05 (2H, m), 6.60 (1H, d, J=3.2 Hz), 7.22 (1H, d, J=1.2 Hz), 7.30(1H, dd, J=2.0, 8.8 Hz), 7.50-7.55 (2H, m), 7.88 (1H, brs), 8.26 (1H, d,J=1.2 Hz), 9.13 (1H, s), 9.29 (1H, s).

The starting material was synthesized by the following method.

Production Example 149-1N1-Dimethyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (101 mg, 0.34mmol, 34%) was obtained as white crystals from6-amino-4-(1H-5-indolylamino)pyrimidine (225.3 mg, 1.0 mmol) and phenylN,N-dimethylcarbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.02 (6H, s), 5.71 (1H, s), 6.23 (2H,brs), 6.60 (1H, d, J=3.6 Hz), 7.22 (1H, dd, J=2.0, 8.8 Hz), 7.50-7.55(2H, m), 7.74 (1H, d, J=2.0 Hz), 8.00 (1H, s), 8.73 (1H, s).

Example 150N1-Dimethyl-5-(6-((3-diethylaminopropyl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (55.3 mg, 0.12 mmol, 66%)was obtained as white crystals fromN1-dimethyl-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (55mg, 0.19 mmol) and 3-diethylaminopropylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (6H, t, J=7.2 Hz), 1.50-1.55(2H, m), 2.30-2.45 (6H, m), 3.00 (6H, s), 3.10-3.15 (2H, m), 6.60 (1H,dd, J=0.8, 3.6 Hz), 6.82 (1H, brs), 7.28 (1H, dd, J=2.0, 8.8 Hz),7.50-7.55 (2H, m), 7.71 (1H, m), 7.84 (1H, brs), 8.23 (1H, d, J=0.8 Hz),9.08 (1H, s), 9.32 (1H, s).

Example 1515-(6-((4-(Pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino-4-pyrimidyl)amino-1H-1-indole-1-carboxylicacid pyrrolidin-1-ylamide

Similarly to Example 28, the title compound (13.1 mg, 0.026 mmol, 14%)was obtained as white crystals from5-(6-amino-4-pyrimidyl)amino-1H-1-indole-1-carboxylic acidpyrrolidin-1-ylamide (61 mg, 0.19 mmol) and4-(pyrrolidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.36 (2H, m), 1.60-1.70 (4H, m),1.70-1.90 (6H, m), 2.40-2.60 (5H, m), 2.85-2.95 (2H, m), 3.40-3.60 (4H,m), 3.95-4.05 (2H, m), 6.59 (1H, d, J=3.2 Hz), 7.22 (1H, brs), 7.28 (1H,dd, J=2.0, 8.8 Hz), 7.60-7.70 (2H, m), 7.87 (1H, m), 8.26 (1H, d, J=1.2Hz), 9.12 (1H, s), 9.28 (1H, s).

The starting material was synthesized by the following method.

Production Example 151-15-(6-Amino-4-pyrimidyl)amino-1H-1-indole-1-carboxylic acidpyrrolidin-1-ylamide

Similarly to Production example 2-3, the title compound (122 mg, 0.38mmol, 38%) was obtained as white crystals from6-amino-4-(1H-5-indolylamino)pyrimidine (225.3 mg, 1.0 mmol) and phenylpyrrolidin-1-ylcarboxylate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.80-1.95 (4H, m), 3.50-3.60 (4H, m),5.71 (1H, s), 6.23 (2H, brs), 6.59 (1H, d, J=3.6 Hz), 7.20 (1H, dd,J=2.0, 8.8 Hz), 7.64-7.69 (2H, m), 7.74 (1H, d, J=2.0 Hz), 8.00 (1H, s),8.73 (1H, s).

Example 1525-(6-((Morpholin-4-yl)carbonyl)amino-4-pyrimidyl)amino-1H-1-indole-1-carboxylicacid pyrrolidin-1-ylamide

Similarly to Example 28, the title compound (30.3 mg, 0.070 mmol, 37%)was obtained as white powder from5-(6-amino-4-pyrimidyl)amino-1H-1-indole-1-carboxylic acidpyrrolidin-1-ylamide (61 mg, 0.19 mmol) and morpholine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.80-1.90 (4H, m), 3.40-3.50 (4H, m),3.50-3.60 (8H, m), 6.59 (1H, d, J=2.8 Hz), 7.24 (1H, d, J=2.0 Hz), 7.28(1H, dd, J=2.0, 8.8 Hz), 7.63-7.69 (2H, m), 7.88 (1H, brs), 8.27 (1H, d,J=2.8 Hz), 9.19 (1H, s), 9.31 (1H, s).

Example 153N1-(2-Propyl)-5-(6-((2-propylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Sodium hydride (48 mg, 1.2 mmol) was suspended in N,N-dimethylformamide(2.5 ml); 6-amino-4-(1H-5-indolylamino)pyrimidine (225.3 mg, 1.0 mmol)was added thereto at room temperature under nitrogen stream; thereaction mixture was stirred for 30 minutes; phenylN-(2-propyl)carbamate (215 mg, 1.2 mmol) was added thereto; and thereaction mixture was stirred overnight. The reaction mixture waspartitioned between a solvent mixture of ethyl acetate-tetrahydrofuran(1:1) and a saturated aqueous solution of sodium hydrogencarbonate; andthe organic layer was washed with water and brine, and dried overanhydrous sodium sulfate. After the solvent was distilled off, theresidue was purified by silica gel column chromatography (eluent; ethylacetate); eluted fractions were concentrated; ethyl acetate was added tothe residue to crystallize; and the crystals were filtered off, anddried under aeration to yield the title compound (31.3 mg, 0.079 mmol,7.9%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.09 (6H, d, J=6.8 Hz), 1.20 (6H, d,J=6.8 Hz), 3.75 (1H, m), 4.00 (1H, m), 6.60 (1H, d, J=3.6 Hz), 6.89 (1H,s), 7.27 (1H, dd, J=2.0, 8.8 Hz), 7.45 (1H, m), 7.80-7.90 (3H, m), 8.11(1H, d, J=8.8 Hz), 8.24 (1H, s), 8.91 (1H, s), 9.31 (1H, s).

The above chromatography was further performed by eluting ethylacetate:methanol=95:5; the eluted fractions were concentrated; ethylacetate-hexane (1:5) was added to the residue to crystallize; and thecrystals were filtered off, and dried under aeration to yieldN1-(2-propyl)-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide(77.8 mg, 0.25 mmol, 25%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.29 (6H, d, J=6.8 Hz), 3.98 (1H, m),5.70 (1H, s), 6.21 (2H, brs), 6.57 (1H, d, J=2.8 Hz), 7.18 (1H, d, J=8.8Hz), 7.72 (1H, s), 7.79-7.82 (2H, m), 7.98 (1H, s), 8.08 (1H, d, J=8.8Hz), 8.72 (1H, s).

Example 154N1-(2-Propyl)-5-(6-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (36.3 mg, 0.074 mmol, 60%)was obtained as white powder fromN1-(2-propyl)-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (38mg, 0.12 mmol) and 4-(pyrrolidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20 (6H, d, J=6.8 Hz), 1.20-1.36(2H, m), 1.60-1.70 (4H, m), 1.70-1.85 (2H, m), 2.40-2.60 (5H, m),2.85-2.95 (2H, m), 3.90-4.10 (3H, m), 6.60 (1H, d, J=3.6 Hz), 7.22 (1H,s), 7.29 (1H, d, J=8.0 Hz), 7.80-8.00 (3H, m), 8.10 (1H, d, J=8.0 Hz),8.26 (1H, s), 9.13 (1H, s), 9.29 (1H, s).

Example 155N1-(2-Propyl)-5-(6-((3-diethylaminopropyl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (27.3 mg, 0.059 mmol, 48%)was obtained as white crystals fromN1-(2-propyl)-5-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (38mg, 0.12 mmol) and 3-diethylaminopropylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.91 (6H, t, J=6.8 Hz), 1.20 (6H, d,J=6.8 Hz), 1.40-1.60 (2H, m), 2.20-2.50 (6H, m), 3.10-3.20 (2H, m), 4.00(1H, m), 6.60 (1H, d, J=3.6 Hz), 6.82 (1H, s), 7.26 (1H, d, J=8.8 Hz),7.70 (1H, m), 7.80-7.85 (3H, m), 8.11 (1H, d, J=8.8 Hz), 8.24 (1H, s),9.08 (1H, s), 9.32 (1H, s).

Example 156N1-Methyl-4-(6-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (21.0 mg, 0.045 mmol, 31%)was obtained as white powder fromN1-methyl-4-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (41 mg,0.15 mmol) and 4-(pyrrolidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.40 (2H, m), 1.60-1.70 (4H, m),1.70-1.85 (2H, m), 2.40-2.60 (5H, m), 2.81 (3H, d, J=4.4 Hz), 2.85-2.95(2H, m), 3.90-4.10 (2H, m), 6.85 (1H, m), 7.18 (1H, t, J=8.0 Hz), 7.35(1H, d, J=4.0 Hz), 7.55 (1H, d, J=8.0 Hz), 7.64 (1H, d, J=8.0 Hz), 7.70(1H, d, J=4.0 Hz), 7.93 (1H, d, J=8.0 Hz), 8.08 (1H, m), 8.26 (1H, s),9.19 (1H, s).

The starting materials were synthesized by the following methods.

Production Example 156-1 6-Chloro-4-(1H-4-indolylamino)pyrimidine

4,6-Dichloropyrimidine (1.01 g, 6.6 mmol), 4-aminoindole (900 mg, 6.6mmol) and N,N-diisopropylethylamine (3.14 ml, 18 mmol) were dissolved inN,N-dimethylformamide (20 ml), and the reaction mixture was stirred at80° C. for 6 hours. The reaction mixture was partitioned between ethylacetate and water; the aqueous layer was subjected to re-extraction withethyl acetate, and the combined organic layer was washed with brine, anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure; and a small amount of methanol was added to theresidue to crystallize; and the crystals were filtered off, washed withmethanol and ethyl acetate, and dried under aeration to yield the titlecompound (599 mg, 2.5 mmol, 37%) as pale brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.49 (1H, brs), 6.75 (1H, brs), 7.10(1H, m), 7.25 (1H, d, J=8.0 Hz), 7.33-7.40 (2H, m), 8.42 (1H, s), 9.71(1H, brs), 11.24 (1H, brs).

Production Example 156-2 6-Amino-4-(1H-4-indolylamino)pyrimidine

A 7N methanol solution of ammonia (50 ml) and tetrahydrofuran (20 ml)were added to 6-chloro-4-(1H-4-indolylamino)pyrimidine (599 mg, 2.5mmol) and the reaction mixture was heated in a sealed tube at 130° C.for 137 hours. The solvent was distilled off under reduced pressure; theresidue was purified by silica gel column chromatography (eluent; ethylacetate:tetrahydrofuran=1:1); diethyl ether was added to the residue tocrystallize; the crystals were filtered off, washed with diethyl ether,and dried under aeration to yield the title compound (454 mg, 2.0 mmol,82%) as pale brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.74 (1H, s), 6.20 (2H, brs), 6.50(1H, m), 7.00 (1H, t, J=8.0 Hz), 7.09 (1H, d, J=8.0 Hz), 7.15-7.30 (2H,m), 7.98 (1H, s), 8.55 (1H, s), 11.06 (1H, brs).

Production Example 156-3N1-Methyl-4-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (124.7 mg, 0.44mmol, 44%) was obtained as pale brown crystals from6-amino-4-(1H-5-indolylamino)pyrimidine (225.3 mg, 1.0 mmol) and phenylN-methylcarbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.81 (3H, d, J=4.0 Hz), 5.75 (1H, s),6.27 (2H, brs), 6.76 (1H, d, J=4.0 Hz), 7.17 (1H, t, J=8.0 Hz), 7.43(1H, d, J=8.0 Hz), 7.70 (1H, d, J=4.0 Hz), 7.92 (1H, d, J=8.0 Hz), 8.00(1H, s), 8.06 (1H, m), 8.70 (1H, s).

Example 157N1-Methyl-4-(6-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (7.7 mg, 0.016 mmol, 11%)was obtained as white powder fromN1-methyl-4-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (41 mg,0.15 mmol) and 4-(piperidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.60 (8H, m), 1.60-1.80 (2H, m),2.30-2.80 (7H, m), 2.81 (3H, d, J=4.4 Hz), 4.05-4.20 (2H, m), 6.85 (1H,m), 7.18 (1H, t, J=8.0 Hz), 7.35 (1H, d, J=4.0 Hz), 7.55 (1H, d, J=8.0Hz), 7.65-7.70 (2H, m), 7.92 (1H, d, J=8.0 Hz), 8.06 (1H, m), 8.26 (1H,s), 9.18 (1H, s).

Example 158N1-Methyl-4-(6-((3-diethylaminopropylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (23.3 mg, 0.053 mmol, 37%)was obtained as white crystals fromN1-methyl-4-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (41 mg,0.15 mmol) and 3-diethylaminopropylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (6H, t, J=6.8 Hz), 1.40-1.60(2H, m), 2.20-2.50 (6H, m), 2.82 (3H, d, J=4.4 Hz), 3.10-3.20 (2H, m),6.80 (1H, m), 6.93 (1H, d, J=6.8 Hz), 7.19 (1H, t, J=8.0 Hz), 7.55 (1H,d, J=8.0 Hz), 7.60-7.70 (2H, m), 7.95 (1H, d, J=8.0 Hz), 8.08 (1H, m),8.23 (1H, s), 9.11 (1H, s), 9.26 (1H, s).

Example 159N1-(4-Fluorophenyl)-4-(6-((3-diethylaminopropylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (28.6 mg, 0.055 mmol, 40%)was obtained as white powder fromN1-(4-fluorophenyl)-4-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide(50 mg, 0.14 mmol) and 3-diethylaminopropylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=6.8 Hz), 1.40-1.60(2H, m), 2.30-2.50 (6H, m), 3.10-3.15 (2H, m), 6.90 (1H, d, J=3.6 Hz),6.97 (1H, m), 7.18-7.26 (3H, m), 7.60-7.70 (4H, m), 7.90-8.00 (2H, m),8.25 (1H, s), 9.13 (1H, s), 9.32 (1H, s), 10.09 (1H, brs).

The starting material was synthesized by the following method.

Production Example 159-1N1-(4-Fluorophenyl)-4-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (109 mg, 0.30mmol, 30%) was obtained as pale yellow powder from6-amino-4-(1H-4-indolylamino)pyrimidine (225.3 mg, 1.0 mmol) and phenylN-(4-fluorophenyl)carbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.78 (1H, s), 6.29 (2H, brs), 6.86(1H, d, J=3.6 Hz), 7.15-7.30 (3H, m), 7.51 (1H, d, J=8.0 Hz), 7.60-7.70(2H, m), 7.89 (1H, d, J=8.0 Hz), 7.92 (1H, d, J=3.6 Hz), 8.01 (1H, s),8.76 (1H, s), 10.07 (1H, s).

Example 160N1-(4-Fluorophenyl)-4-(6-((2-diethylaminoethylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (36.1 mg, 0.072 mmol, 52%)was obtained as white crystals fromN1-(4-fluorophenyl)-4-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide(50 mg, 0.14 mmol) and 2-diethylaminoethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, t, J=6.8 Hz), 2.30-2.50(6H, m), 3.10-3.20 (2H, m), 6.91 (1H, d, J=3.6 Hz), 6.99 (1H, m),7.18-7.26 (3H, m), 7.60-7.75 (4H, m), 7.90-8.00 (2H, m), 8.25 (1H, s),9.24 (1H, s), 9.31 (1H, s), 10.09 (1H, brs).

Example 161N1-Methyl-6-(6-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (35.6 mg, 0.077 mmol, 43%)was obtained as white crystals fromN1-methyl-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (51 mg,0.18 mmol) and 4-(pyrrolidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.40 (2H, m), 1.60-1.70 (4H, m),1.70-1.85 (2H, m), 2.40-2.60 (5H, m), 2.81 (3H, d, J=4.0 Hz), 2.85-2.95(2H, m), 3.90-4.10 (2H, m), 6.57 (1H, d, J=3.6 Hz), 7.23 (1H, s),7.39-7.50 (2H, m), 7.68 (1H, d, J=3.6 Hz), 8.02 (1H, m), 8.26 (1H, s),8.51 (1H, s), 9.13 (1H, s), 9.40 (1H, s).

The starting materials were synthesized by the following methods.

Production Example 161-1 6-Chloro-4-(1H-6-indolylamino)pyrimidine

The title compound (1.229 g, 5.0 mmol, 46%) was obtained as pale yellowcrystals from 4,6-dichloropyrimidine (1.69 g, 11 mmol), 6-aminoindoleand N,N-diisopropylethylamine by the method similar to the synthesis of6-chloro-4-(1H-5-indolylamino)pyrimidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.39 (1H, s), 6.74 (1H, s), 7.02 (1H,dd, J=2.8, 8.8 Hz), 7.30 (1H, t, J=2.8 Hz), 7.50 (1H, d, J=8.8 Hz), 7.83(1H, m), 8.43 (1H, s), 9.78 (1H, s), 11.07 (1H, brs).

Production Example 161-2 6-Amino-4-(1H-6-indolylamino)pyrimidine

A 7N ammonia in methanol solution (75 ml) was added to6-chloro-4-(1H-6-indolylamino)pyrimidine (1.229 g, 5.0 mmol); and thereaction mixture was heated in a sealed tube at 130° C. for 6 days. Thesolvent was distilled off under reduced pressure; the residue waspurified by silica gel column chromatography (eluent; ethylacetate:tetrahydrofuran=1:1); diethyl ether was added to the residue tocrystallize; the crystals were filtered off, and washed with diethylether, and dried under aeration to yield the title compound (883 mg, 3.9mmol, 78%) as pale yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.71 (1H, s), 6.19 (2H, brs), 6.32(1H, s), 6.92 (1H, dd, J=1.2, 8.0 Hz), 7.20 (1H, m), 7.40 (1H, d, J=8.0Hz), 7.65 (1H, s), 7.98 (1H, s), 8.65 (1H, s), 10.91 (1H, s).

Production Example 161-3N1-Methyl-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (105 mg, 0.37mmol, 48%) was obtained as pale brown crystals from6-amino-4-(1H-6-indolylamino)pyrimidine (175 mg, 0.78 mmol) and phenylN-methylcarbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.80 (3H, d, J=4.4 Hz), 5.73 (1H, s),6.24 (2H, brs), 6.56 (1H, d, J=2.8 Hz), 7.33 (1H, d, J=8.4 Hz), 7.44(1H, d, J=8.4 Hz), 7.66 (1H, d, J=2.8 Hz), 7.90-8.10 (2H, m), 8.33 (1H,s), 8.84 (1H, s).

Example 162N1-Methyl-6-(6-((3-diethylaminopropylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (37.3 mg, 0.085 mmol, 47%)was obtained as white crystals fromN1-methyl-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (51 mg,0.18 mmol) and 3-diethylaminopropylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (6H, t, J=6.8 Hz), 1.40-1.60(2H, m), 2.20-2.40 (6H, m), 2.81 (3H, d, J=4.0 Hz), 3.05-3.20 (2H, m),6.58 (1H, d, J=4.0 Hz), 6.83 (1H, s), 7.38 (1H, d, J=8.0 Hz), 7.46 (1H,d, J=8.0 Hz), 7.60-7.80 (2H, m), 8.03 (1H, m), 8.23 (1H, s), 8.46 (1H,s), 9.10 (1H, s), 9.43 (1H, s).

Example 163N1-(2-Propyl)-6-(6-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (40.4 mg, 0.082 mmol, 54%)was obtained as white crystals fromN1-(2-propyl)-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (47mg, 0.15 mmol) and 4-(pyrrolidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20 (6H, d, J=6.8 Hz), 1.20-1.36(2H, m), 1.60-1.70 (4H, m), 1.70-1.85 (2H, m), 2.40-2.60 (5H, m),2.80-3.00 (2H, m), 3.90-4.10 (3H, m), 6.56 (1H, d, J=3.6 Hz), 7.24 (1H,s), 7.30-7.50 (2H, m), 7.74 (1H, d, J=3.6 Hz), 7.81 (1H, d, J=8.8 Hz),8.26 (1H, s), 8.50 (1H, s), 9.13 (1H, s), 9.39 (1H, s).

The starting material was synthesized by the following method.

Production Example 163-1N1-(2-Propyl)-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (95.3 mg, 0.31mmol, 40%) was obtained as pale brown crystals from6-amino-4-(1H-6-indolylamino)pyrimidine (175 mg, 0.78 mmol) and phenylN-(2-propyl)carbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20 (6H, d, J=6.4 Hz), 4.00 (1H, m),5.73 (1H, s), 6.24 (2H, brs), 6.55 (1H, d, J=3.6 Hz), 7.33 (1H, dd,J=2.0, 8.0 Hz), 7.44 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=3.6 Hz), 7.80(1H, d, J=8.0 Hz), 7.98 (1H, s), 8.33 (1H, s), 8.84 (1H, s).

Example 164N1-(2-Propyl)-6-(6-((3-diethylaminopropylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (40.1 mg, 0.086 mmol, 57%)was obtained as white crystals fromN1-(2-propyl)-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (47mg, 0.15 mmol) and 3-diethylaminopropylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (6H, t, J=6.8 Hz), 1.20 (6H, d,J=6.4 Hz), 1.40-1.60 (2H, m), 2.20-2.50 (6H, m), 3.05-3.20 (2H, m), 4.00(1H, m), 6.57 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.36 (1H, dd, J=8.0 Hz),7.46 (1H, d, J=8.0 Hz), 7.12 (1H, m), 7.76 (1H, d, J=3.6 Hz), 7.82 (1H,d, J=8.0 Hz), 8.23 (1H, s), 8.44 (1H, s), 9.10 (1H, s), 9.43 (1H, s).

Example 165N1-(4-Fluorophenyl)-6-(6-((3-diethylaminopropylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (22.9 mg, 0.044 mmol, 24%)was obtained as white crystals fromN1-(4-fluorophenyl)-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide(67 mg, 0.19 mmol) and 3-diethylaminopropylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (6H, t, J=6.8 Hz), 1.40-1.60(2H, m), 2.20-2.40 (6H, m), 3.05-3.20 (2H, m), 6.68 (1H, d, J=3.6 Hz),6.87 (1H, s), 7.24 (2H, t, J=8.8 Hz), 7.43 (1H, dd, J=2.0, 8.4 Hz), 7.52(1H, d, J=8.4 Hz), 7.60-7.80 (4H, m), 7.89 (1H, d, J=3.6 Hz), 8.23(1H,s), 8.48 (1H, s), 9.11 (1H, s), 9.45 (1H, s).

The starting material was synthesized by the following method.

Production Example 165-1N1-(4-Fluorophenyl)-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (137 mg, 0.38mmol, 49%) was obtained as pale brown crystals from6-amino-4-(1H-6-indolylamino)pyrimidine (175 mg, 0.78 mmol) and phenylN-(4-fluorophenyl)carbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.75 (1H, s), 6.26 (2H, brs), 6.66(1H, d, J=3.6 Hz), 7.22 (2H, t, J=8.8 Hz), 7.39 (1H, dd, J=2.0, 8.4 Hz),7.49 (1H, d, J=8.4 Hz), 7.60-7.70 (2H, m), 7.87 (1H, d, J=3.6 Hz), 7.99(1H, s), 8.36 (1H, s), 8.91 (1H, s), 10.01 (1H, s).

Example 166N1-(4-Fluorophenyl)-6-(6-((2-diethylaminoethylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (11.1 mg, 0.022 mmol, 12%)was obtained as white crystals fromN1-(4-fluorophenyl)-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide(67 mg, 0.19 mmol) and 2-diethylaminoethylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.80-1.00 (6H, m), 2.20-2.50 (6H, m),3.00-3.20 (2H, m), 6.74 (1H, s), 6.84 (1H, d, J=3.6 Hz), 7.03 (1H, d,J=8.0 Hz), 7.20 (2H, t, J=8.8 Hz), 7.50-7.70 (3H, m), 7.70 (1H, d, J=8.0Hz), 8.00 (1H, s), 8.12 (1H, d, J=3.6 Hz), 8.37 (1H, s), 9.23 (1H, s),9.41 (1H, s), 10.12 (1H, s).

Example 167N1-Dimethyl-6-(6-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (16.1 mg, 0.034 mmol, 17%)was obtained as pale yellow powder fromN1-dimethyl-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (58mg, 0.20 mmol) and 4-(pyrrolidin-1-yl)piperidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.36 (2H, m), 1.60-1.70 (4H, m),1.70-1.85 (2H, m), 2.40-2.60 (5H, m), 2.80-3.00 (2H, m), 3.02 (6H, s),3.90-4.10 (2H, m), 6.55 (1H, s), 7.26 (1H, s), 7.30 (1H, d, J=8.0 Hz),7.40-7.50 (2H, m), 8.01 (1H, s), 8.29 (1H, s), 9.16 (1H, s), 9.41 (1H,s).

The starting material was synthesized by the following method.

Production Example 167-1N1-Dimethyl-6-(6-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (58.3 mg, 0.20mmol, 25%) was obtained as pale brown crystals from6-amino-4-(1H-6-indolylamino)pyrimidine (175 mg, 0.78 mmol) and phenylN,N-dimethylcarbamate.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.01 (6H, s), 5.72 (1H, s), 6.26 (2H,brs), 6.54 (1H, d, J=3.6 Hz), 7.24 (1H, dd, J=2.0, 8.0 Hz), 7.40-7.50(2H, m), 7.84 (1H, s), 8.01 (1H, s), 8.86 (1H, s).

Example 168N1-Diethyl-5-(2-((pyrrolidin-1-ylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (91.0 mg, 0.22 mmol, 38%)was obtained as pale yellow powder fromN1-diethyl-5-(2-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (186mg, 0.57 mmol) and pyrrolidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.15 (6H, t, J=6.8 Hz), 1.60-1.90(4H, m), 3.20-3.50 (8H, m), 6.28 (1H, d, J=6.0 Hz), 6.52 (1H, d, J=3.6Hz), 7.40-7.50 (3H, m), 7.96 (1H, d, J=6.0 Hz), 8.24 (1H, brs), 8.67(1H, s), 9.35 (1H, s).

The starting materials were synthesized by the following methods.

Production example 168-1 2-Amino-4-(1H-5-indolylamino)pyrimidine

A mixture of 2-amino-4,6-dichloropyrimidine (1.64 g, 10 mmol),5-aminoindole (1.32 g, 10 mmol), diisopropylethylamine (5.23 ml, 30mmol) and N,N-dimethylformamide (30 ml) was heated at 60° C. and stirredovernight under nitrogen atmosphere. The reaction mixture waspartitioned between ethyl acetate and water after cooled to roomtemperature; and the organic layer was washed with water and brine, anddried over anhydrous sodium sulfate. The solvent was distilled off; theobtained residue was dissolved in tetrahydrofuran (100 ml); 10%Palladium on carbon (50% wet, 1.0 g) was added thereto under nitrogenatmosphere; and the reaction mixture was stirred for 4 days underhydrogen atmosphere at atmospheric pressure. The reaction system waspurged with nitrogen; the catalyst was filtered off; the filtrate wasconcentrated under reduced pressure; the residue was purified by NHsilica gel column chromatography (eluent; ethyl acetate:methanol=95:5);diethyl ether was added to the residue to crystallize; and the crystalswere filtered off, and dried under aeration to yield the title compound(852 mg, 3.8 mmol, 38%) as pale brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.89 (1H, d, J=5.6 Hz), 5.99 (2H,brs), 6.34 (1H, s), 7.12 (1H, d, J=8.4 Hz), 7.20-7.40 (2H, m), 7.70 (1H,d, J=5.6 Hz), 7.79 (1H, s), 8.73 (1H, s), 10.95 (1H, s).

Production Example 168-2N1-Diethyl-5-(2-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Production example 2-3, the title compound (1.22 g, 3.8mmol, quantitative) was obtained as pale brown powder from2-amino-4-(1H-5-indolylamino)pyrimidine (852 mg, 3.8 mmol) anddiethylcarbamyl chloride.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.26 (6H, t, J=7.2 Hz), 3.49 (4H, q,J=7.2 Hz), 4.78 (2H, brs), 6.03 (1H, d, J=5.6 Hz), 6.57 (1H, d, J=3.6Hz), 6.66 (1H, s), 7.16 (1H, dd, J=2.0, 8.8 Hz), 7.31 (1H, d, J=3.6 Hz),7.53 (1H, d, J=2.0 Hz), 7.65 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=5.6 Hz).

Example 169N1-Diethyl-5-(5-iodo-2-((pyrrolidin-1-ylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (37.3 mg, 0.068 mmol, 26%)was obtained as white powder fromN1-diethyl-5-(2-amino-5-iodopyrimidin-4-yl)amino-1H-1-indolecarboxamide(117 mg, 0.26 mmol) and pyrrolidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.15 (6H, t, J=6.8 Hz), 1.60-1.80(4H, m), 3.30-3.50 (8H, m), 6.54 (1H, s), 7.30-7.60 (3H, m), 8.09 (1H,s), 8.15 (1H, s), 8.33 (1H, s), 8.82 (1H, s).

The starting material was synthesized by the following method.

Production Example 169-1N1-Diethyl-5-(2-amino-5-iodopyrimidin-4-yl)amino-1H-1-indolecarboxamide

N1-Diethyl-5-(2-aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide (1.06g, 3.27 mmol) was dissolved in N,N-dimethylformamide (10 ml) undernitrogen atmosphere; N-iodosuccinimide (920 mg, 4.08 mmol) was addedthereto while cooling with an ice water bath; and the reaction mixturewas stirred at room temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water; and the organic layer waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was distilled off; and the residue was purified by silicagel column chromatography (eluent; ethyl acetate) to yield the titlecompound (1.00 g, 2.33 mmol, 68%) as yellow powder.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.26 (6H, t, J=7.2 Hz), 3.49 (4H, q,J=7.2 Hz), 4.84 (2H, brs), 6.58 (1H, d, J=3.6 Hz), 6.95 (1H, s),7.27-7.40 (2H, m), 7.63 (1H, d, J=8.8 Hz), 7.82 (1H, s), 8.16 (1H, s).

Example 170N1-Diethyl-5-(5-cyano-2-((pyrrolidin-1-ylamino)carbonyl)aminopyrimidin-4-yl)amino-1H-1-indolecarboxamide

Similarly to Example 28, the title compound (35.3 mg, 0.079 mmol, 28%)was obtained as white crystals fromN1-diethyl-5-(2-amino-5-cyanopyrimidin-4-yl)amino-1H-1-indolecarboxamide(100 mg, 0.29 mmol) and pyrrolidine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.15 (6H, t, J=6.8 Hz), 1.60-1.80(4H, m), 3.20-3.50 (8H, m), 6.56 (1H, s), 7.40-7.60 (3H, m), 8.03 (1H,s), 8.49 (1H, s), 9.43 (1H, s), 9.50 (1H, s).

The starting material was synthesized as follows.

Production Example 170-1N1-Diethyl-5-(2-amino-5-cyanopyrimidin-4-yl)amino-1H-1-indolecarboxamide

N1-Diethyl-5-(2-amino-5-iodopyrimidin-4-yl)amino-1H-1-indolecarboxamide(882 mg, 1.96 mmol) was dissolved in N,N-dimethylformamide (10 ml) undernitrogen atmosphere; zinc cyanide (253 mg, 2.15 mmol) andtetrakis(triphenylphosphine)palladium (226 mg, 0.2 mmol) was addedthereto; the reaction mixture was stirred at 100° C. for 2 hours. Thereaction mixture was partitioned between ethyl acetate and water; andthe organic layer was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was distilled off; and the residuewas purified by silica gel column chromatography (eluent; ethyl acetate)to yield the title compound (493 mg, 1.41 mmol, 72%) as white crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm) 1.26 (6H, t, J=7.2 Hz), 3.49 (4H, q,J=7.2 Hz), 5.26 (2H, brs), 6.59 (1H, d, J=3.6 Hz), 7.05 (1H, s),7.27-7.35 (2H, m), 7.66 (1H, d, J=8.8 Hz), 7.78 (1H, m), 8.27 (1H, s).

Example 171 5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acid(2-diethylaminoethyl)amide

Similarly to Production example 5-1, a crude product of5-(2-aminopyridin-4-yloxy)indole-1-carboxylic acid(2-diethylaminoethyl)amide (81 mg) was obtained as a pale yellow oilfrom 4-(1H-5-indolyloxy)-2-pyridinamine (225 mg, 1.00 mmol, WO02/32872), sodium hydride (80 mg, 2.00 mmol, 60% in oil), and phenylN-(2-diethylaminoethyl)carbamate (314 mg, 1.50 mmol). Similarly toProduction example 5-2, a mixture ofphenyl(4-(1-(2-diethylaminoethyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-(2-diethylaminoethyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)carbamate(32 mg) was obtained as a pale yellow oil from the crude productobtained above, phenyl chloroformate (0.041 ml, 0.33 mmol) andtriethylamine (0.049 ml, 0.35 mmol). Similarly to Example 5, the titlecompound (11 mg, 0.025 mmol, 12%) was obtained as pale yellow crystalsfrom the mixture obtained above, ethylamine hydrochloride (30 mg, 0.26mmol) and triethylamine (0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.97 (6H, t, J=7.0 Hz), 1.02 (3H, t,J=7.0 Hz), 2.44-2.60 (8H, m), 3.10 (2H, m), 6.50 (1H, dd, J=1.6, 6.0Hz), 6.68 (1H, d, J=3.6 Hz), 6.86 (1H, d, J=1.6 Hz), 7.03 (1H, dd,J=2.0, 8.8 Hz), 7.36 (1H, d, J=2.0 Hz), 7.89 (1H, d, J=3.6 Hz), 7.97(1H, m), 8.02 (1H, d, J=6.0 Hz), 8.17 (1H, m), 8.28 (1H, d, J=8.8 Hz),9.00 (1H, s).

ESI-MS: 439.30 (M+H).

The starting material was synthesized as follows.

Production Example 171-1 Phenyl N-(2-diethylaminoethyl)carbamate

Similarly to Production example 2-1, a crude product was obtained from2-diethylaminoethylamine (7.3 ml, 50 mmol) and phenyl chloroformate (6.9ml, 55 mmol). The crude product was purified by silica gel columnchromatography (Fuji Silysia NH, ethyl acetate), and further purified bysilica gel column chromatography (Fuji Silysia NH; hexane:ethylacetate=3:1, 1:1, ethyl acetate in this order) to yield the titlecompound (1.3 g, 6.4 mmol, 13%) as a colorless oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.04 (6H, t, J=7.2 Hz), 2.52-2.62 (6H,m), 3.31 (2H, q, J=5.6 Hz), 5.62 (1H, brs), 7.13 (2H, d, J=7.6 Hz), 7.18(1H, t, J=7.6 Hz), 7.35 (2H, t, J=7.6 Hz).

Example 172 5-(2-(3,3-Diethylureido)pyridin-4-yloxy)indole-1-carboxylicacid (2-ethoxyethyl)amide

Similarly to Production example 5-2, a mixture ofphenyl(4-(1-(2-ethoxyethyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-(2-ethoxyethyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)carbamate(3.42 g) was obtained as a pale yellow oil from5-(2-aminopyridin-4-yloxy)indole-1-carboxylic acid (2-ethoxyethyl)amide(1.86 g, 5.46 mmol), phenyl chloroformate (1.51 ml, 12.0 mmol) andtriethylamine (1.90 ml, 13.7 mmol). Similarly to Example 5, the titlecompound was obtained as pale pink crystals (84 mg, 0.19 mmol) from thisintermediates (174 mg) and diethylamine (0.16 ml, 1.5 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.01 (6H, t, J=7.2 Hz), 1.11 (3H, t,J=7.2 Hz), 3.26-3.31 (4H, m), 3.42-3.50 (4H, m), 3.53 (2H, m), 6.54 (1H,dd, J=2.4, 5.6 Hz), 6.68 (1H, d, J=3.6 Hz), 7.04 (1H, dd, J=2.4, 9.0Hz), 7.36 (1H, d, J=2.4 Hz), 7.41 (1H, d, J=2.4 Hz), 7.93 (1H, d, J=3.6Hz), 8.06 (1H, d, J=5.6 Hz), 8.28 (1H, d, J=9.0 Hz), 8.31 (1H, m), 8.60(1H, s).

ESI-MS: 440.47 (M+H).

The starting materials were synthesized as follows.

Production Example 172-1 Phenyl N-(2-ethoxyethyl)carbamate

Similarly to Example 5, a crude product was obtained from2-ethoxyethylamine (5.2 ml, 50 mmol), phenyl chloroformate (6.9 ml, 55mmol), and pyridine (4.5 ml, 55 mmol). The obtained crude product waspurified by silica gel column chromatography (Fuji Silysia BW-300,hexane:ethyl acetate=85:15 to 50:50) to yield the title compound (8.38g, 40.4 mmol, 80.9%) as a pale yellow oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.23 (3H, t, J=7.0 Hz), 3.44-3.48 (2H,m), 3.52-3.58 (4H, m), 5.41 (1H, brs), 7.13 (2H, d, J=7.6 Hz), 7.19 (1H,t, J=7.6 Hz), 7.35 (2H, t, J=7.6 Hz).

Production Example 172-2 5-(2-Aminopyridin-4-yloxy)indole-1-carboxylicacid (2-ethoxyethyl)amide

Similarly to Production example 5-1, the title compound (1.86 g, 5.46mmol, 61.5%) was obtained as a pale brown oil from4-(1H-5-indolyloxy)-2-pyridinamine (2.00 g, 8.88 mmol, WO 02/32872),sodium hydride (462 mg, 11.5 mmol, 60% in oil), and phenylN-(2-ethoxyethyl)carbamate (2.23 g, 10.7 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.11 (3H, t, J=7.2 Hz), 3.42 (2H, m),3.47 (2H, q, J=7.2 Hz), 3.53 (2H, t, J=6.0 Hz), 5.74 (1H, d, J=2.0 Hz),5.84 (2H, m), 6.12 (1H, dd, J=2.0, 6.0 Hz), 6.67 (1H, d, J=3.8 Hz), 7.01(1H, dd, J=2.0, 8.8 Hz), 7.33 (1H, d, J=2.0 Hz), 7.75 (1H, d, J=6.0 Hz),7.91 (1H, d, J=6.0 Hz), 8.26 (1H, d, J=8.8 Hz), 8.28 (1H, m).

Example 173 5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acid(2-ethoxyethyl)amide

Similarly to Example 5, the title compound was obtained as colorlesscrystals (84 mg, 0.204 mmol) from a mixture (174 mg) ofphenyl(4-(1-(2-ethoxyethyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-(2-ethoxyethyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)carbamate,which was obtained as an intermediate in Example 172, ethylaminehydrochloride (122 mg, 1.50 mmol) and triethylamine (0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.02 (3H, t, J=7.0 Hz), 1.12 (3H, t,J=7.0 Hz), 3.10 (2H, m), 3.40-3.49 (4H, m), 3.53 (2H, t, J=5.8 Hz), 6.50(1H, dd, J=2.4, 5.8 Hz), 6.68 (1H, d, J=3.6 Hz), 6.86 (1H, d, J=2.4 Hz),7.04 (1H, dd, J=2.4, 8.8 Hz), 7.37 (1H, d, J=2.4 Hz), 7.93 (1H, d, J=3.6Hz), 7.96 (1H, m), 8.02 (1H, d, J=5.8 Hz), 8.28 (1H, d, J=8.8 Hz), 8.31(1H, m), 9.00 (1H, s).

ESI-MS: 412.18 (M+H).

Example 174 5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acid(3-ethoxypropyl)amide

Similarly to Production example 5-2, a mixture ofphenyl(4-(1-(3-ethoxypropyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-(3-ethoxypropyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)carbamatewas obtained as a pale brown oil (720 mg) from5-(2-Aminopyridin-4-yloxy)indole-1-carboxylic acid (3-ethoxypropyl)amide(900 mg, 2.54 mmol), phenyl chloroformate (0.669 ml, 5.33 mmol) andtriethylamine (0.885 ml, 6.35 mmol). Similarly to Example 5, the titlecompound was obtained as pale pink crystals (41 mg, 0.096 mmol) fromthis intermediate (100 mg) ethylamine hydrochloride (64 mg, 0.841 mmol)and triethylamine (0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.02 (3H, t, J=7.2 Hz), 1.10 (3H, t,J=7.2 Hz), 1.79 (2H, m), 3.10 (2H, m), 3.34 (2H, m), 3.42 (4H, m), 6.50(1H, dd, J=2.4, 5.8 Hz), 6.67 (1H, d, J=3.8 Hz), 6.86 (1H, d, J=2.4 Hz),7.03 (1H, dd, J=2.4, 9.2 Hz), 7.36 (1H, d, J=2.4 Hz), 7.90 (1H, d, J=3.8Hz), 7.95 (1H, m), 8.02 (1H, d, J=5.8 Hz), 8.20 (1H, m), 8.28 (1H, m),8.99 (1H, s).

ESI-MS: 426.39 (M+H).

The starting material was synthesized as follows.

Production Example 174-1 5-(2-Aminopyridin-4-yloxy)indol-1-carboxylicacid (3-ethoxypropyl)amide

Similarly to Production example 5-1, the title compound (900 mg, 2.54mmol, 57.2%) was obtained as a pale brown oil from4-(1H-5-indolyloxy)-2-pyridinamine (1.00 g, 4.44 mmol, WO 02/32872),sodium hydride (213 mg, 5.33 mmol, 60% in oil), and phenylN-(3-ethoxypropyl)carbamate (1.19 g, 5.33 mmol, WO 02/32872).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.07-1.13 (3H, m), 1.81 (2H, m),3.33-3.47 (6H, m), 5.76 (1H, d, J=2.4 Hz), 5.85 (2H, s), 6.14 (1H, dd,J=2.4, 6.0 Hz), 6.68 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz),7.34 (1H, d, J=2.4 Hz), 7.77 (1H, d, J=6.0 Hz), 7.90 (1H, d, J=3.6 Hz),8.20 (1H, m), 8.27 (1H, d, J=8.8 Hz).

Example 175 5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acid(3-methylsulphanylpropyl)amide

Similarly to Production example 5-1, a crude product of5-(2-aminopyridin-4-yloxy)indole-1-carboxylic acid(3-methylsulfanylpropyl)amide (105 mg) was obtained as a pale yellow oilfrom 4-(1H-5-indolyloxy)-2-pyridinamine (125 mg, 0.555 mmol, WO02/32872), sodium hydride (28 mg, 0.694 mmol, 60% in oil), and phenylN-(3-methylsulfanylpropyl)carbamate (156 mg, 0.694 mmol, WO 02/32872).Similarly to Production example 5-2, a mixture ofphenyl(4-(1-(3-methylsulfanylpropyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-(3-methylsulfanylpropyl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)carbamatewas obtained as a pale yellow oil from the crude product obtained above,phenyl chloroformate (0.10 ml, 0.76 mmol) and triethylamine (0.12 ml,0.83 mmol). Similarly to Example 5, the title compound (17 mg, 0.040mmol) was obtained as colorless crystals from the mixture obtainedabove, ethylamine hydrochloride (141 mg, 1.73 mmol) and triethylamine(0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.02 (3H, t, J=7.2 Hz), 1.83 (2H, m),2.05 (3H, s), 2.52 (2H, t, J=7.6 Hz), 3.10 (2H, m), 3.35 (2H, m), 6.50(1H, d, J=5.6 Hz), 6.68 (1H, d, J=3.4 Hz), 6.86 (1H, s), 7.03 (1H, d,J=9.2 Hz), 7.36 (1H, s), 7.91 (1H, d, J=3.4 Hz), 7.94 (1H, m), 8.02 (1H,d, J=5.6 Hz), 8.24 (1H, m), 8.27 (1H, d, J=9.2 Hz), 8.99 (1H, s).

Example 176 5-(2-(3,3-Diethylureido)pyridin-4-yloxy)indole-1-carboxylicacid thiazol-2-ylamide

Similarly to Production example 5-2, a mixture (267 mg) ofphenyl(4-(1-(thiazol-2-yl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-(thiazol-2-yl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)carbamatewas obtained as a pale yellow oil from5-(2-aminopyridin-4-yloxy)indole-1-carboxylic acid thiazol-2-ylamide(145 mg, 0.413 mmol), phenyl chloroformate (0.110 ml, 0.909 mmol), andtriethylamine (0.140 ml, 1.03 mmol). Similarly to Example 5, the titlecompound (74 mg, 0.16 mmol) was obtained as pale pink crystals from theintermediate obtained above (131 mg) and diethylamine (0.120 ml, 1.11mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.01 (6H, t, J=6.8 Hz), 3.28 (4H, m),6.56 (1H, dd, J=2.0, 5.6 Hz), 6.66 (1H, m), 7.06 (2H, m), 7.37 (1H, d,J=2.0 Hz), 7.43 (1H, s), 7.47 (1H, d, J=4.4 Hz), 8.05 (1H, m), 8.07 (1H,d, J=5.6 Hz), 8.60 (2H, m).

ESI-MS: 451.15 (M+H).

The starting material was synthesized as follows.

Production Example 176-1 5-(2-Aminopyridin-4-yloxy)indole-1-carboxylicacid thiazol-2-ylamide

Similarly to Production example 5-1, the title compound (145 mg, 0.413mmol, 57.2%) was obtained as a pale brown oil from4-(1H-5-indolyloxy)-2-pyridinamine (225 mg, 1.00 mmol, WO 02/32872),sodium hydride (120 mg, 3.00 mmol, 60% in oil) and phenylN-(thiazol-2-yl)carbamate (286 mg, 1.30 mmol, WO 02/32872).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.77 (1H, d, J=2.4 Hz), 5.87 (2H,brs), 6.15 (1H, dd, J=2.4, 5.6 Hz), 6.65 (1H, d, J=3.6 Hz), 7.03 (1H,dd, J=2.4, 9.0 Hz), 7.07 (1H, d, J=4.6 Hz), 7.34 (1H, d, J=2.4 Hz), 7.46(1H, d, J=4.6 Hz), 7.77 (1H, d, J=5.6 Hz), 8.04 (1H, d, J=3.6 Hz), 8.58(1H, d, J=9.0 Hz).

Example 177 5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acidthiazol-2-ylamide

Similarly to Example 5, the title compound (71 mg, 0.168 mmol) wasobtained as colorless crystals from a mixture (135 mg) ofphenyl(4-(1-(thiazol-2-yl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-(thiazol-2-yl)carbamoyl-1H-indol-5-yloxy)pyridin-2-yl)carbamateobtained in Example 176, ethylamine hydrochloride (91 mg, 1.1 mmol), andtriethylamine (0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.07 (3H, t, J=7.2 Hz), 3.07-3.14(2H, m), 6.51 (1H, dd, J=2.0, 6.0 Hz), 6.61 (1H, s), 7.01 (2H, m), 7.35(1H, s), 7.41 (1H, m), 8.01-8.06 (3H, m), 8.05 (1H, m), 8.62 (1H, d,J=9.2 Hz), 9.00 (1H, s).

ESI-MS: 423.23 (M+H).

Example 1781-Ethyl-3-(4-(1-((4-methylpiperazin-1-yl)carbonyl)-1H-indol-5-yloxy)pyridin-2-yl)urea

Similarly to Production example 5-2, a mixture (1.09 g) ofphenyl(4-(1-((4-methylpiperazin-1-yl)carbonyl)-1H-indol-5-yloxy)pyridin-2-yl)-(N-phenoxycarbonyl)carbamateandphenyl(4-(1-((4-methylpiperazin-1-yl)carbonyl)-1H-indol-5-yloxy)pyridin-2-yl)carbamatewas obtained as a colorless amorphous solid from(5-(2-aminopyridin-4-yloxy)indol-1-yl)-(4-methylpiperazin-1-yl)methanone(0.66 g, 1.9 mmol), phenyl chloroformate (0.52 ml, 4.2 mmol), andtriethylamine (0.66 ml, 4.8 mmol). Similarly to Example 5, the titlecompound (41 mg, 0.097 mmol) was obtained as colorless crystals from theintermediate obtained above (177 mg), ethylamine hydrochloride (0.122 g,1.50 mmol) and triethylamine (0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.03 (3H, t, J=6.0 Hz), 2.21 (3H, s),2.39 (4H, m), 3.12 (2H, m), 3.51 (4H, m), 6.51 (1H, dd, J=2.4, 5.6 Hz),6.67 (1H, d, J=3.4 Hz), 6.86 (1H, d, J=2.4 Hz), 7.04 (1H, dd, J=2.4, 8.8Hz), 7.39 (1H, d, J=2.4 Hz), 7.61 (1H, d, J=3.4 Hz), 7.70 (1H, d, J=8.8Hz), 8.02 (1H, m), 8.03 (1H, d, J=8.8 Hz), 9.00 (1H, s).

ESI-MS: 423.27(M+H).

The starting materials were synthesized as follows.

Production Example 178-1 Phenyl(4-methylpiperazin-1-yl)carboxylate

Similarly to Production example 2-1, crystals were obtained from1-methylpiperazine (5.5 ml, 50 mmol), phenyl chloroformate (6.9 ml, 55mmol), and pyridine (4.5 ml, 55 mmol). The obtained crystals weresuspended in diethylether:hexane=2:1, filtered off, washed with hexane,and dried to yield the title compound (9.7 g, 44 mmol, 88%) as an oilwith pale orange color.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.20 (3H, s), 2.34 (4H, m), 3.40 (2H,m), 3.56 (2H, m), 7.09 (2H, d, J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.36(2H, t, J=7.6 Hz).

Production Example 178-2(5-(2-Aminopyridin-4-yloxy)indol-1-yl)-(4-methylpiperazin-1-yl)methanone

Similarly to Production example 5-1, a crude product was obtained from4-(1H-5-indolyloxy)-2-pyridinamine (2.00 g, 8.88 mmol, WO 02/32872),sodium hydride (462 mg, 11.5 mmol, 60% in oil) andphenyl(4-methylpiperazin-1-yl)carboxylate (2.35 g, 10.7 mmol). Theobtained crude product was purified by silica gel column chromatography(Fuji Silysia NH; hexane:ethyl acetate=3:7, ethyl acetate, ethylacetate:methanol=9:1 in this order) to yield the title compound (0.66 g,1.9 mmol, 21%) as a colorless amorphous solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.20 (3H, s), 2.39 (4H, m), 3.51 (4H,m), 5.75 (1H, d, J=2.0 Hz), 5.84 (2H, m), 6.13 (1H, dd, J=2.0, 6.0 Hz),6.66 (1H, d, J=3.2 Hz), 7.02 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4Hz), 7.59 (1H, d, J=3.2 Hz), 7.68 (1H, d, J=8.8 Hz), 7.76 (1H, d, J=6.0Hz).

Example 1791-Ethyl-3-(4-(1-(morpholin-4-ylcarbonyl)-1H-indol-5-yloxy)pyridin-2-yl)urea

Similarly to Production example 5-2, a crude product was obtained from5-(2-aminopyridin-4-yloxy)indol-1-yl)-(morpholin-4-yl)methanone (0.60 g,1.8 mmol), phenyl chloroformate (0.49 ml, 3.9 mmol), and triethylamine(0.62 ml, 4.4 mmol). The obtained crude product was filtrated by silicagel filtration (Fuji Silysia BW-300, ethyl acetate) and concentratedunder reduced pressure to yield a mixture (1.11 g) ofphenyl(4-(1-(morpholin-4-ylcarbonyl)-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-(morpholine-4-ylcarbonyl)-1H-indol-5-yloxy)pyridin-2-yl)carbamateas a pale yellow oil. Similarly to Example 5, the title compound (73 mg,0.178 mmol) was obtained as colorless crystals from the intermediateobtained above (173 mg), ethylamine hydrochloride (122 mg, 1.50 mmol)and triethylamine (0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.03 (3H, t, J=7.2 Hz), 3.07-3.14(2H, m), 3.52 (4H, m), 3.68 (4H, m), 6.50 (1H, dd, J=2.4, 6.0 Hz), 6.68(1H, d, J=3.2 Hz), 6.87 (1H, d, J=2.4 Hz), 7.05 (1H, dd, J=2.4, 8.8 Hz),7.40 (1H, d, J=2.4 Hz), 7.64 (1H, d, J=3.2 Hz), 7.73 (1H, d, J=8.8 Hz),8.00 (1H, m), 8.03 (1H, d, J=6.0 Hz), 9.01 (1H, s).

ESI-MS: 410.57 (M+H).

The starting materials were synthesized as follows.

Production Example 179-1 Phenyl(morpholin-4-yl)carboxylate

Similarly to Production example 2-1, a crude product was obtained frommorpholine (4.4 ml, 50 mmol), phenyl chloroformate (6.9 ml, 55 mmol),and pyridine (4.5 ml, 55 mmol). The obtained crude product was purifiedby silica gel column chromatography (Fuji Silysia BW-300; hexane:ethylacetate=85:15, 60:40 in this order) to yield the title compound (8.9 g,43 mmol, 86%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.57 (2H, brs), 3.68 (2H, brs), 3.75(4H, m), 7.11 (2H, d, J=7.6 Hz), 7.21 (1H, t, J=7.6 Hz), 7.37 (2H, t,J=7.6 Hz).

Production Example 179-2(5-(2-Aminopyridin-4-yloxy)indol-1-yl)-(morpholin-4-yl)methanone

Similarly to Production example 5-1, a crude product was obtained from4-(1H-5-indolyloxy)-2-pyridinamine (2.00 g, 8.88 mmol, WO 02/32872),sodium hydride (462 mg, 11.5 mmol, 60% in oil) andphenyl(morpholin-4-yl)carboxylate (2.21 g, 10.7 mmol). The obtainedcrude product was purified by silica gel column chromatography (FujiSilysia NH, hexane:ethyl acetate=2:3 or ethyl acetate), and furtherpurified by silica gel column chromatography (Fuji Silysia BW-300,hexane:ethyl acetate=2:3, ethyl acetate, or ethyl acetate:methanol=9:1)to yield the title compound (0.60 g, 1.8 mmol, 20%) as colorlesscrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.52 (4H, m), 3.68 (4H, m), 5.77 (1H,d, J=2.4 Hz), 5.83 (2H, brs), 6.13 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d,J=3.2 Hz), 7.02 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.61(1H, d, J=3.2 Hz), 7.71 (1H, d, J=8.8 Hz), 7.76 (1H, d, J=5.6 Hz).

Example 1801,1-Diethyl-3-(4-(1-(morpholin-4-ylcarbonyl)-1H-indol-5-yloxy)pyridin-2-yl)urea

Similarly to Example 5, the title compound (85 mg, 0.194 mmol) wasobtained as colorless crystals from a mixture (173 mg) ofphenyl(4-(1-(morpholin-4-ylcarbonyl)-1H-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-(morpholin-4-ylcarbonyl)-1H-indol-5-yloxy)pyridin-2-yl)carbamatesynthesized as intermediate in Example 179, and diethylamine (0.16 ml,1.50 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.01 (6H, t, J=6.8 Hz), 3.30 (4H, m),3.53 (4H, m), 3.68 (4H, m), 6.54 (1H, d, J=6.0 Hz), 6.68 (1H, d, J=3.4Hz), 7.05 (1H, dd, J=2.0, 8.8 Hz), 7.39 (1H, d, J=2.0 Hz), 7.43 (1H, s),7.64 (1H, d, J=3.4 Hz), 7.73 (1H, d, J=8.8 Hz), 8.07 (1H, d, J=6.0 Hz),8.62 (1H, s).

ESI-MS: 438.25 (M+H).

Example 181 5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acidpiperidin-4-ylamide

Similarly to Production example 5-1, a crude product of t-butyl4-((5-(2-aminopyridin-4-yloxy)indole-1-carbonyl)amino)piperidine-1-carboxylatewas obtained from 4-(1H-5-indolyloxy)-2-pyridinamine (144 mg, 0.639mmol, WO 02/32872), sodium hydride (29 mg, 0.735 mmol, 60% in oil), andt-butyl(4-phenoxycarbonylaminopiperidin-1-yl)carboxylate (215 mg, 0.671mmol). A reaction similar to Production example 5-2 was performed usingthe entire amount of this crude product, phenyl chloroformate (0.20 ml,1.6 mmol) and triethylamine (0.22 ml); and the solvent was distilled offunder reduced pressure after the reaction was completed. A reactionsimilar to Example 5 was performed using the entire amount of theresidue, ethylamine hydrochloride (260 mg, 3.92 mmol) and triethylamine(0.5 ml); the organic layer was partitioned between ethyl acetate andwater, washed with brine, and dried over anhydrous sodium sulfate; andthe solvent was distilled off under reduced pressure. The residue wasdissolved in trifluoroacetate (3.0 ml); the reaction mixture was stirredat room temperature for 15 minutes, and concentrated; and the residuewas partitioned between ethyl acetate and water. The organic layer waswashed with brine and dried over anhydrous sodium sulfate; the solventwas distilled off under reduced pressure; the residue was purified bysilica gel column chromatography (Fuji Silysia NH, ethylacetate:methanol=98:2 to 75:25). The obtained crystals were suspended indiethyl ether and filtered off, washed with diethyl ether, and dried toyield the title compound (43 mg, 0.10 mmol, 16%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.02 (3H, t, J=7.2 Hz), 1.37-1.49(2H, m), 1.80 (2H, m), 2.48 (2H, m), 2.95 (2H, m), 3.10 (2H, m), 3.71(1H, m), 6.50 (1H, dd, J=2.4, 6.0 Hz), 6.66 (1H, d, J=3.4 Hz), 6.86 (1H,d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz),7.90-8.01 (3H, m), 8.02 (1H, d, J=6.0 Hz), 8.26 (1H, d, J=8.8 Hz), 8.99(1H, s).

ESI-MS: 423.26 (M+H).

The starting material was synthesized as follows.

Production Example 181-1t-Butyl(4-phenoxycarbonylaminopiperidin-1-yl)carboxylate

A reaction similar to Production example 2-1 using t-Butyl4-aminopiperidin-1-ylcarboxylate (328 mg, 1.64 mmol), phenylchloroformate (0.226 ml, 1.80 mmol) and pyridine (0.146 ml, 1.80 mmol);and the obtained crystals were suspended in hexane:ethyl acetate=4:1,filtered off, and the filtrate was purified by silica gel columnchromatography (Fuji Silysia BW-300, hexane:ethyl acetate=4:1 to 1:1).The purified crystals were then suspended in hexane:ethyl acetate=4:1and filtered off. The title compound (215 mg, 0.617 mmol, 40.9%) wasobtained as colorless crystals, together with the previously obtainedcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.22-1.34 (2H, m), 1.38 (9H, s), 1.77(2H, m), 2.83 (2H, m), 3.51 (1H, m), 3.84 (2H, m), 7.08 (2H, d, J=7.6Hz), 7.18 (1H, t, J=7.6 Hz), 7.35 (2H, t, J=7.6 Hz), 7.78 (1H, d, J=8.0Hz).

ESI-MS: 343.15 (M+Na).

Example 182 5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acid(1-methylpiperidin-4-yl)amide

5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acidpiperidin-4-ylamide (36 mg, 0.085 mmol, Example 181) was dissolved intetrahydrofuran (2.0 ml) and methanol (1.0 ml); and a 37% aqueousformaldehyde solution (0.036 ml, 0.43 mmol) and acetic acid (0.0098 ml,0.17 mmol) were added thereto. While stirring at room temperature,sodium triacetoxyborohydride (27 mg, 0.13 mmol) was added; and thereaction mixture was stirred for 30 minutes. The reaction mixture waspartitioned between ethyl acetate and a saturated aqueous solution ofsodium hydrogencarbonate; and the organic layer was washed with brineand dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure; the obtained crystals were suspended in diethylether, filtered off, washed with diethyl ether, and dried to yield thetitle compound (25 mg, 0.057 mmol, 67%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.02 (3H, t, J=7.2 Hz), 1.54-1.68(2H, m), 1.83 (2H, m), 1.96 (2H, m), 2.16 (3H, s), 2.78 (2H, m), 3.10(2H, m), 3.64 (1H, m), 6.50 (1H, dd, J=2.4, 6.0 Hz), 6.66 (1H, d, J=3.6Hz), 6.86 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d,J=2.4 Hz), 7.95 (1H, d, J=3.6 Hz), 7.97 (2H, m), 8.02 (1H, d, J=6.0 Hz),8.25 (1H, d, J=8.8 Hz), 8.99 (1H, m).

ESI-MS: 437.37 (M+H).

Example 1835-(2-(N-Methyl-(4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)indole-1-carboxylicacid methylamide

5-(2-(Methylamino)pyridin-4-yloxy)indole-1-carboxylic acid methylamide(70 mg, 0.24 mmol) was dissolved in tetrahydrofuran (7.0 ml);triethylamine (0.039 ml) and 4-nitrophenylchloroformate (57 mg, 0.28mmol) were added thereto one by one; and the reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture waspartitioned between ethyl acetate and water; and the organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate andbrine, then dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(2.0 ml); 4-(pyrrolidin-1-yl)piperidine (43 mg, 0.28 mmol) was addedthereto; and the reaction mixture was stirred at room temperature for 24hours. The reaction mixture was partitioned between ethyl acetate andwater; and the organic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia NH,hexane-ethyl acetate-methanol system); the obtained oil was solidifiedwith hexane; the obtained solid was then suspended in hexane, filteredoff, washed with hexane, and dried to yield the title compound (51 mg,0.11 mmol, 45%) as pale yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.13-1.30 (2H, m), 1.65 (6H, m), 2.02(1H, m), 2.42 (4H, m), 2.72 (2H, m), 2.83 (3H, d, J=4.0 Hz), 3.08 (3H,s), 3.53 (2H, m), 6.23 (1H, s), 6.51 (1H, d, J=6.0 Hz), 6.66 (1H, d,J=3.4 Hz), 7.04 (1H, d, J=9.0 Hz), 7.36 (1H, s), 7.87 (1H, d, J=3.4 Hz),8.11 (1H, d, J=6.0 Hz), 8.15 (1H, m), 8.29 (1H, d, J=9.0 Hz).

ESI-MS: 477.38 (M+H).

The starting material was synthesized as follows.

Production Example 183-15-(2-(Methylamino)pyridin-4-yloxy)indole-1-carboxylic acid methylamide

N1-Methyl-5-(2-aminopyridin-4-yl)oxy-1H-1-indolecarboxamide (5.00 g,17.7 mmol, Production example 5-1) was dissolved in ethanol (170 ml) andN,N-dimethylformamide (40 ml); 1H-benzotriazole-1-methanol (2.64 g, 17.7mmol) was added thereto; and the reaction mixture was heated to refluxfor 2 hours. After allowing to be cooled to room temperature, sodiumborohydride (1.49 g, 35.4 mmol) was added to the reaction mixture; thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was partitioned between ethyl acetate and water; andthe organic layer was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia BW-300,hexane-ethyl acetate-methanol system). The obtained crystals weresuspended in acetone: diethyl ether =1:3, filtered off, washed withhexane, and dried to yield the title compound (1.05 g, 3.55 mmol, 20.1%)as pale yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.66 (3H, d, J=4.8 Hz), 2.82 (3H, d,J=4.0 Hz), 5.76 (1H, d, J=2.0 Hz), 6.10 (1H, dd, J=2.0, 6.0 Hz), 6.36(1H, m), 6.65 (1H, d, J=4.0 Hz), 7.00 (1H, dd, J=2.4, 8.8 Hz), 7.31 (1H,d, J=2.4 Hz), 7.83 (2H, m), 8.13 (1H, m), 8.26 (1H, d, J=8.8 Hz).

Example 184 5-(2-(1-Methylureido)pyridin-4-yloxy)indole-1-carboxylicacid methylamide

4-NitrophenylN-methyl-(4-(1-methylcarbamoyl-indol-5-yloxy)pyridin-2-yl)carbamate (105mg, 0.228 mmol) was dissolved in N,N-dimethylformamide (2.5 ml); aqueousammonia (0.5 ml, 28.0%) was added thereto; the reaction mixture wasstirred at room temperature for 10.5 hours. The reaction mixture waspartitioned between ethyl acetate and water; and the organic layer waswashed with brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained crystals were suspended inethanol:diethyl ether=1:1 (6 ml), filtered off, washed with diethylether, and dried to yield the title compound (37 mg, 0.11 mmol, 48%) aspale yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.83 (3H, d, J=4.0 Hz), 3.19 (3H, s),6.51 (1H, d, J=5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.07 (1H,d, J=9.0 Hz), 7.39 (1H, s), 7.87 (1H, d, J=3.6 Hz), 8.14 (2H, m), 8.29(1H, d, J=9.0 Hz).

ESI-MS: 340.07 (M+H).

The starting material was synthesized as follows.

Production Example 184-1 4-NitrophenylN-methyl-(4-(1-methylcarbamoyl-indol-5-yloxy)pyridin-2-yl)carbamate

5-(2-(Methylamino)pyridin-4-yloxy)indole-1-carboxylic acid methylamide(200 mg, 0.675 mmol) synthesized in Production example 183-1 wasdissolved in tetrahydrofuran (20 ml); triethylamine (0.100 ml, 0.742mmol) and 4-nitrophenylchloroformate (150 mg, 0.742 mmol) was addedthereto one by one; and the reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was partitioned betweenethyl acetate and water; and the organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Fuji Silysia BW-300, hexane-ethyl acetate system) to yield the titlecompound (210 mg, 0.455 mmol, 67.4%) as a pale yellow oil.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.82 (3H, d, J=4.4 Hz), 3.46 (3H, s),6.62 (1H, d, J=3.6 Hz), 6.83 (1H, dd, J=2.0, 5.6 Hz), 7.03 (1H, dd,J=2.0, 8.4 Hz), 7.24 (1H, d, J=2.0 Hz), 7.37 (1H, d, J=2.0 Hz), 7.41(2H, d, J=9.2 Hz), 7.85 (1H, d, J=3.6 Hz), 8.14 (1H, m), 8.22 (2H, d,J=9.2 Hz), 8.23 (1H, d, J=8.4 Hz), 8.32 (1H, d, J=5.6 Hz).

Example 1855-(2-(3,3-Diethyl-1-methylureido)pyridin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Example 184, the title compound (14 mg, 0.035 mmol, 16%)was obtained as a colorless amorphous solid from 4-nitrophenylN-methyl-(4-(1-methylcarbamoyl-indol-5-yloxy)pyridin-2-yl)carbamate (105mg, 0.228 mmol, Production example 184-1) and diethylamine (0.028 ml,0.27 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.80 (6H, t, J=6.4 Hz), 2.83 (3H, d,J=3.2 Hz), 3.03 (3H, s), 3.07 (4H, m), 6.11 (1H, s), 6.49 (1H, m), 6.66(1H, s), 7.02 (1H, d, J=9.0 Hz), 7.35 (1H, s), 7.86 (1H, s), 8.09 (1H,d, J=5.6 Hz), 8.15 (1H, m), 8.28 (1H, d, J=9.0 Hz).

ESI-MS: 396.18 (M+H).

Example 1865-(2-(3-Ethyl-1-methylureido)pyridin-4-yloxy)indole-1-carboxylic acidmethylamide

Similarly to Production example 27-2, phenylN-methyl-(4-(1-methylcarbamoyl-indol-5-yloxy)pyridin-2-yl)carbamate (324mg, 0.778 mmol) was obtained as a colorless amorphous solid from5-(2-(methylamino)pyridin-4-yloxy)indole-1-carboxylic acid methylamide(500 mg, 1.69 mmol), phenyl chloroformate (0.23 ml, 1.9 mmol) andtriethylamine (0.26 ml, 1.9 mmol). This intermediate (125 mg, 0.300mmol) was dissolved in N,N-dimethylformamide (2.5 ml)-triethylamine (0.5ml); ethylamine hydrochloride (122 mg, 1.50 mmol) was added thereto; andthe reaction mixture was stirred at room temperature overnight, and thenstirred at 80° C. for 1.5 hours. Ethylamine hydrochloride (122 mg, 1.50mmol) was added thereto; the reaction mixture was stirred at 80° C. for2 hours; ethylamine hydrochloride (122 mg, 1.50 mmol) and triethylamine(0.5 ml) were further added thereto; and the reaction mixture wasstirred at 80° C. for 0.5 hours, and then stirred at room temperaturefor 2 days. The reaction mixture was partitioned between ethyl acetate(100 ml) and water (50 ml); and the organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Fuji Silysia BW-300, hexane:ethyl acetate=3:2, then ethyl acetate); theobtained crystals were suspended in diethyl ether (10 ml)-hexane (50ml), filtered off, and dried to yield the title compound (41 mg, 0.11mmol) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) (ppm): 1.04 (3H, t, J=7.2 Hz), 2.83 (3H, d,J=4.4 Hz), 3.15 (2H, m), 3.19 (3H, s), 6.51 (1H, dd, J=2.4, 6.6 Hz),6.67 (1H, d, J=4.0 Hz), 6.77 (1H, d, J=2.4 Hz), 7.07 (1H, dd, J=2.4, 8.8Hz), 7.39 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=4.0 Hz), 8.15 (1H, d, J=6.0Hz), 8.16 (1H, m), 8.29 (1H, d, J=8.8 Hz), 9.27 (1H, m).

ESI-MS: 368.13 (M+H).

Example 187 6-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acidmethylamide

Similarly to Example 5, the title compound (54 mg, 0.15 mmol, 80%) wasobtained as colorless crystals fromphenyl(4-(1-methylcarbamoyl-1H-indol-6-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamate(100 mg, 0.19 mmol), ethylamine hydrochloride (78 mg, 0.96 mmol) andtriethylamine (0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.03 (3H, t, J=7.2 Hz), 2.79 (3H, d,J=4.4 Hz), 3.07-3.14 (2H, m), 6.52 (1H, dd, J=2.4, 5.8 Hz), 6.71 (1H, d,J=3.6 Hz), 6.88 (1H, d, J=2.4 Hz), 6.99 (1H, dd, J=2.4, 8.4 Hz), 7.65(1H, d, J=8.4 Hz), 7.84 (1H, d, J=3.6 Hz), 7.96 (2H, m), 8.04 (1H, d,J=5.8 Hz), 8.16 (1H, m), 9.02 (1H, s).

ESI-MS: 354.15 (M+H), 376.16 (M+Na).

The starting materials were synthesized as follows.

Production Example 187-1 4-(1H-Indol-6-yloxy)pyridin-2-ylamine

Sodium hydride (1.04 g, 26.0 mmol, 60% in oil) was suspended in dimethylsulfoxide (2.5 ml); 6-hydroxyindole (3.46 g, 26.0 mmol) and2-amino-4-chloropyridine (2.57 g, 20.0 mmol, WO 02/332872) weresubsequently added thereto at room temperature under nitrogen stream;and the reaction mixture was stirred at 160° C. for 8.5 hours. Aftercooled down to room temperature, the reaction mixture was partitionedbetween ethyl acetate (150 ml) and a solvent mixture of aqueousammonia:water=1:1 (50 ml); the organic layer was washed with a solventmixture of aqueous ammonia:water=1:1, and with brine, dried overanhydrous sodium sulfate, and concentrated. The residue was purified bysilica gel column chromatography (Fuji Silysia BW-300, ethyl acetate, orethyl acetate:methanol=93:7); and the obtained crystals were suspendedin diethyl ether, filtered off, washed with diethyl ether, and dried toyield the title compound (477 mg, 2.12 mmol, 10.6%) as pale yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.76 (1H, s), 5.82 (2H, brs), 6.13(1H, d, J=6.0 Hz), 6.44 (1H, s), 6.75 (1H, d, J=8.4 Hz), 7.10 (1H, s),7.34 (1H, s), 7.56 (1H, d, J=8.4 Hz), 7.75 (1H, d, J=6.0 Hz), 11.12 (1H,brs).

Production Example 187-2 6-(2-Aminopyridin-4-yloxy)indole-1-carboxylicacid methyl amide

Similarly to Production example 5-1, the title compound (315 mg, 1.12mmol, 87.9%) was obtained as colorless crystals from4-(1H-indol-6-yloxy)pyridin-2-ylamine (285 mg, 1.27 mmol), sodiumhydride (63 mg, 1.58 mmol, 60% in oil) and phenyl N-methylcarbamate (239mg, 1.58 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.80 (3H, d, J=4.4 Hz), 5.77 (1H, d,J=2.0 Hz), 5.85 (2H, m), 6.14 (1H, dd, J=2.0, 5.6 Hz), 6.69 (1H, d,J=3.6 Hz), 6.96 (1H, dd, J=2.0, 8.4 Hz), 7.63 (1H, d, J=8.4 Hz), 7.77(1H, d, J=5.6 Hz), 7.81 (1H, d, J=3.6 Hz), 7.94 (1H, d, J=2.0 Hz), 8.13(1H, d, J=4.4 Hz).

Production Example 187-3Phenyl(4-(1-methylcarbamoyl-1H-indol-6-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamate

Similarly to Production example 5-2, the title compound (404 mg, 0.77mmol, 69%) was obtained as pale pink crystals from6-(2-aminopyridin-4-yloxy)indole-1-carboxylic acid methylamide (315 mg,1.12 mmol), triethylamine (0.51 ml, 3.7 mmol), and phenyl chloroformate(0.42 ml, 3.4 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.78 (3H, d, J=4.4 Hz), 6.74 (1H, d,J=3.6 Hz), 7.02 (1H, dd, J=2.4, 5.6 Hz), 7.05 (1H, dd, J=2.4, 8.4 Hz),7.16 (4H, d, J=7.8 Hz), 7.29 (2H, t, J=7.8 Hz), 7.42 (4H, t, J=7.8 Hz),7.52 (1H, m), 7.69 (1H, d, J=8.4 Hz), 7.86 (1H, d, J=3.6 Hz), 8.04 (1H,d, J=2.4 Hz), 8.15 (1H, m), 8.44 (1H, d, J=5.6 Hz).

Example 188 6-(2-(3,3-Diethylureido)pyridin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (55 mg, 0.14 mmol, 76%) wasobtained as colorless crystals fromphenyl(4-(1-methylcarbamoyl-1H-indol-6-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamate(100 mg, 0.19 mmol) and diethylamine (0.10 ml, 0.96 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.01 (6H, t, J=7.2 Hz), 2.79 (3H, d,J=4.4 Hz), 3.26-3.32 (4H, m), 6.56 (1H, dd, J=2.0, 5.6 Hz), 6.71 (1H, d,J=3.6 Hz), 6.99 (1H, dd, J=2.0, 8.8 Hz), 7.42 (1H, d, J=2.0 Hz), 7.65(1H, d, J=8.8 Hz), 7.84 (1H, d, J=3.6 Hz), 7.96 (1H, d, J=2.0 Hz), 8.08(1H, d, J=5.6 Hz), 8.15 (1H, m), 8.63 (1H, s).

ESI-MS: 382.21 (M+H).

Example 1896-(2-(3-(2-Diethylaminoethyl)ureido)pyridin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (51 mg, 0.12 mmol, 63%) wasobtained as pale yellow crystals fromphenyl(4-(1-methylcarbamoyl-1H-indol-6-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamate(100 mg, 0.19 mmol) and 2-diethylaminoethylamine (0.14 ml, 0.96 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.6 Hz), 2.41-2.49(6H, m), 2.79 (3H, d, J=4.0 Hz), 3.14 (2H, m), 6.51 (1H, dd, J=2.4, 6.0Hz), 6.71 (1H, d, J=3.6 Hz), 6.84 (1H, d, J=2.4 Hz), 6.99 (1H, dd,J=2.4, 8.2 Hz), 7.65 (1H, d, J=8.2 Hz), 7.84 (1H, d, J=3.6 Hz), 7.96(1H, d, J=2.4 Hz), 8.02 (1H, d, J=6.0 Hz), 8.16 (2H, m), 9.13 (1H, s).

ESI-MS: 425.29 (M+H).

Example 1906-(2-(((4-(Pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (72 mg, 0.16 mmol, 82%) wasobtained as colorless crystals fromphenyl(4-(1-methylcarbamoyl-1H-indol-6-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl)carbamate(100 mg, 0.19 mmol) and 4-(pyrrolidin-1-yl)piperidine (148 mg, 0.96mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.19-1.31 (2H, m), 1.63 (4H, m), 1.76(2H, m), 2.09 (1H, m), 2.44 (4H, m), 2.79 (3H, d, J=4.0 Hz), 2.82 (2H,m), 3.92 (2H, m), 6.55 (1H, dd, J=2.4, 5.6 Hz), 6.71 (1H, d, J=3.8 Hz),6.98 (1H, dd, J=2.4, 8.8 Hz), 7.32 (1H, d, J=2.4 Hz), 7.65 (1H, d, J=8.8Hz), 7.84 (1H, d, J=3.8 Hz), 7.96 (1H, d, J=2.4 Hz), 8.08 (1H, d, J=5.6Hz), 8.15 (1H, m), 9.12 (1H, s).

ESI-MS: 436.32 (M+H).

Example 191 6-(6-(3-Ethylureido)pyrimidin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Production example 5-2, an intermediate,phenyl(4-(1-methylcarbamoyl-1H-indol-6-yloxy)pyrimidin-6-yl)-N-(phenoxycarbonyl)carbamate,was obtained as pale yellow crystals (597 mg) from6-(6-aminopyrimidin-4-yloxy)indole-1-carboxylic acid methylamide (245mg, 0.865 mmol), triethylamine (0.40 ml, 2.9 mmol), and phenylchloroformate (0.33 ml, 2.6 mmol). Similarly to Example 5, the titlecompound (43 mg, 0.12 mmol) was obtained as colorless crystals from thisintermediate (143 mg), ethylamine hydrochloride (88 mg, 1.1 mmol), andtriethylamine (0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.03 (3H, t, J=6.8 Hz), 2.80 (3H, s),3.10 (2H, m), 6.71 (1H, s), 6.99 (1H, d, J=8.4 Hz), 7.01 (1H, s), 7.04(1H, m), 7.62 (1H, d, J=8.4 Hz), 7.84 (1H, s), 7.98 (1H, s), 8.16 (1H,m), 8.36 (1H, s), 9.45 (1H, s).

ESI-MS: 355.27 (M+H), 377.26 (M+Na).

The starting material was synthesized as follows.

Production Example 191-1 6-(1H-Indol-6-yloxy)pyrimidin-4-ylamine

Sodium hydride (200 mg, 5.00 mmol) was suspended in dimethyl sulfoxide(8 ml); while stirring at room temperature, 6-hydroxyindole (666 mg,5.00 mmol) and 6-amino-4-chloropyrimidine (518 mg, 4.00 mmol) were addedthereto one by one; and the reaction mixture was stirred at 60° C. for 2hours, at 80° C. for 1 hour, and at 100° C. for 1.5 hours. After cooleddown to room temperature, the reaction mixture was partitioned betweenethyl acetate and water; and the organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated. The residue waspurified by silica gel column chromatography (Fuji Silysia BW-300,hexane:ethyl acetate=1:1, ethyl acetate, then ethylacetate:methanol=98:2); the obtained crystals were suspended in ethylacetate (50 ml) and stirred at room temperature overnight, filtered off,washed with diethyl ether, and dried to yield the title compound (322mg, 1.42 mmol, 35.6%) as pale yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.56 (1H, s), 6.44 (1H, s), 6.72 (2H,s), 6.76 (1H, d, J=8.4 Hz), 7.12 (1H, s), 7.34 (1H, s), 7.55 (1H, d,J=8.4 Hz), 8.05 (1H, s), 11.13 (1H, brs).

Production Example 191-2 6-(6-Aminopyrimidin-4-yloxy)indole-1-carboxylicacid methyl amide

Similarly to Production example 5-1, the title compound (245 mg, 0.865mmol, 61.3%) was obtained as colorless crystals from6-(1H-indol-6-yloxy)pyrimidin-4-ylamine (320 mg, 1.41 mmol), sodiumhydride (68 mg, 1.7 mmol, 60% in oil), and phenyl N-methylcarbamate (257mg, 1.70 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.80 (3H, d, J=4.4 Hz), 5.64 (1H, s),6.69 (1H, d, J=3.6 Hz), 6.77 (2H, s), 6.96 (1H, dd, J=2.0, 8.4 Hz), 7.61(1H, d, J=8.4 Hz), 7.81 (1H, d, J=3.6 Hz), 7.94 (1H, d, J=2.0 Hz), 8.05(1H, s), 8.12 (1H, m).

Example 1926-(6-(3,3-Diethylureido)pyrimidin-4-yloxy)indole-1-carboxylic acidmethylamide

Similarly to Example 5, the title compound (63 mg, 0.16 mmol) wasobtained as milky white crystals from the intermediate obtained inExample 191 (149 mg) and diethylamine (0.11 ml, 1.1 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.03 (6H, t, J=7.2 Hz), 2.80 (3H, d,J=4.4 Hz), 3.33 (4H, q, J=7.2 Hz), 6.71 (1H, d, J=3.8 Hz), 7.00 (1H, dd,J=2.0, 8.4 Hz), 7.31 (1H, s), 7.62 (1H, d, J=8.4 Hz), 7.83 (1H, d, J=3.8Hz), 7.98 (1H, d, J=2.0 Hz), 8.15 (1H, m), 8.38 (1H, s), 9.31 (1H, s).

ESI-MS: 383.23 (M+H), 405.26 (M+Na).

Example 1936-(6-(3-(2-Diethylaminoethyl)ureido)pyrimidin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (63 mg, 0.15 mmol) wasobtained as grayish white crystals from the intermediate obtained inExample 191 (164 mg) and 2-diethylaminoethylamine (0.15 ml, 1.1 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.0 Hz), 2.44 (6H, m),2.80 (3H, d, J=4.0 Hz), 3.13 (2H, m), 6.70 (1H, d, J=3.6 Hz), 6.90 (2H,m), 7.43 (1H, brs), 7.62 (1H, d, J=8.4 Hz), 7.83 (1H, d, J=3.6 Hz), 7.98(1H, d, J=1.6 Hz), 8.15 (1H, m), 8.34 (1H, s), 9.63 (1H, s).

ESI-MS: 426.31 (M+H).

Example 1946-(6-(((4-Pyrrolidin-1-yl)piperidin-1-ylcarbonyl)amino)pyrimidin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (59 mg, 0.13 mmol) wasobtained as colorless crystals from the intermediate obtained in Example191 (141 mg) and 4-(pyrrolidin-1-yl)piperidine (167 mg, 1.08 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.22-1.34 (2H, m), 1.64 (4H, m), 1.78(2H, m), 2.12 (1H, m), 2.44 (4H, m), 2.80 (3H, d, J=4.0 Hz), 2.88 (2H,m), 3.93 (2H, m), 6.70 (1H, d, J=3.6 Hz), 6.99 (1H, dd, J=2.0, 8.4 Hz),7.20 (1H, s), 7.62 (1H, d, J=8.4 Hz), 7.83 (1H, d, J=3.6 Hz), 7.97 (1H,d, J=2.0 Hz), 8.15 (1H, m), 8.38 (1H, s), 9.73 (1H, s).

ESI-MS: 464.36 (M+H).

Example 195 4-(6-(3-Ethylureido)pyrimidin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Production example 5-2, an intermediate (a mixture ofphenyl(4-(1-methylcarbamoyl-1H-indol-4-yloxy)pyrimidin-6-yl)-N-(phenoxycarbonyl)carbamateandphenyl(4-(1-methylcarbamoyl-1H-indol-4-yloxy)pyrimidin-6-yl)carbamate,379 mg) was obtained as pale yellow crystals from4-(6-Aminopyrimidin-4-yloxy)indole-1-carboxylic acid methylamide (245mg, 0.865 mmol), triethylamine (0.40 ml, 2.9 mmol) and phenylchloroformate (0.33 ml, 2.6 mmol). Similarly to Example 5, the titlecompound (41 mg, 0.12 mmol) was obtained as a colorless crystal fromthis intermediate (94 mg), ethylamine hydrochloride (78 mg, 0.96 mmol),and triethylamine (0.5 ml).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.03 (3H, t, J=7.4 Hz), 2.82 (3H, d,J=4.0 Hz), 3.12 (2H, m), 6.40 (1H, d, J=3.8 Hz), 6.98 (1H, d, J=8.0 Hz),7.05 (1H, s), 7.28 (1H, t, J=8.0 Hz), 7.31 (1H, m), 7.76 (1H, d, J=3.8Hz), 8.14 (1H, d, J=8.0 Hz), 8.17 (1H, m), 8.33 (1H, m), 9.48 (1H, s).

ESI-MS: 355.20 (M+H), 377.25 (M+Na).

The starting materials were synthesized as follows.

Production Example 195-1 6-(1H-Indol-4-yloxy)pyrimidin-4-ylamine

The title compound (568 mg, 2.51 mmol, 41.8%) was obtained as grayishwhite crystals by performing a reaction similar to that in Productionexample 191-1 using 6-amino-4-chloropyrimidine (777 mg, 6.00 mmol),4-hydroxyindole (999 mg, 7.50 mmol) and sodium hydride (300 mg, 7.50mmol) at 100° C. for 6 hours.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.56 (1H, s), 6.13 (1H, m), 6.70 (2H,brs), 6.74 (1H, d, J=8.0 Hz), 7.09 (1H, t, J=8.0 Hz), 7.29 (2H, m), 8.05(1H, s), 11.28 (1H, s).

Production Example 195-2 4-(6-Aminopyrimidin-4-yloxy)indole-1-carboxylicacid methyl amide

Similarly to Production example 5-1, the title compound (279 mg, 0.985mmol, 74.0%) was obtained as colorless crystals from6-(1H-indol-4-yloxy)pyrimidin-4-ylamine (300 mg, 1.33 mmol), sodiumhydride (83 mg, 2.1 mmol, 60% in oil), and phenyl N-methylcarbamate (314mg, 2.07 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.82 (3H, d, J=4.4 Hz), 5.64 (1H, s),6.39 (1H, d, J=3.6 Hz), 6.77 (2H, brs), 6.94 (1H, d, J=8.0 Hz), 7.27(1H, t, J=8.0 Hz), 7.75 (1H, d, J=3.6 Hz), 8.04 (1H, s), 8.12 (1H, d,J=8.0 Hz), 8.15 (1H, m).

Example 1964-(6-(3,3-Diethylureido)pyrimidin-4-yloxy)indole-1-carboxylic acidmethylamide

Similarly to Example 5, the title compound (54 mg, 0.14 mmol) wasobtained as colorless crystals from the intermediate obtained in Example195 (94 mg) and diethylamine (0.10 ml, 0.96 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.04 (6H, t, J=6.8 Hz), 2.82 (3H, d,J=4.0 Hz), 3.34 (4H, q, J=6.8 Hz), 6.41 (1H, d, J=3.8 Hz), 6.98 (1H, d,J=8.0 Hz), 7.28 (1H, t, J=8.0 Hz), 7.36 (1H, s), 7.76 (1H, d, J=3.8 Hz),8.14 (1H, d, J=8.0 Hz), 8.17 (1H, m), 8.35 (1H, s), 9.34 (1H, s).

ESI-MS: 383.31 (M+H), 405.22 (M+Na).

Example 1974-(6-(3-(2-Diethylaminoethyl)ureido)pyrimidin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (49 mg, 0.12 mmol) wasobtained as colorless crystals from the intermediate obtained in Example195 (94 mg) and 2-diethylaminoethylamine (0.14 ml, 0.96 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.0 Hz), 2.45 (6H, m),2.82 (3H, d, J=4.0 Hz), 3.14 (2H, m), 6.40 (1H, d, J=3.4 Hz), 6.98 (1H,d, J=8.0 Hz), 7.04 (1H, s), 7.28 (1H, t, J=8.0 Hz), 7.45 (1H, m), 7.76(1H, d, J=3.4 Hz), 8.14 (1H, d, J=8.0 Hz), 8.17 (1H, m), 8.32 (1H, s),8.65 (1H, brs).

ESI-MS: 426.27 (M+H).

Example 1984-(6-(((4-(Pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyrimidin-4-yloxy)indole-1-carboxylicacid methylamide

Similarly to Example 5, the title compound (57 mg, 0.12 mmol) wasobtained as colorless crystals from the intermediate obtained in Example195 (94 mg) and 4-(pyrrolidin-1-yl)piperidine (148 mg, 0.96 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.22-1.35 (2H, m), 1.64 (4H, m), 1.78(2H, m), 2.13 (1H, m), 2.45 (4H, m), 2.82 (3H, d, J=3.2 Hz), 2.89 (2H,m), 3.94 (2H, m), 6.40 (1H, m), 6.98 (1H, d, J=8.0 Hz), 7.26 (1H, s),7.28 (1H, t, J=8.0 Hz), 7.76 (1H, m), 8.13 (1H, d, J=8.0 Hz), 8.16 (1H,m), 8.35 (1H, s), 9.35 (1H, s).

ESI-MS: 464.35 (M+H).

Example 1995-(2-(3-(3-Diethylaminopropyl)ureido)pyridin-4-ylamino)indole-1-carboxylicacid methylamide

1-(4-Chloropyridin-2-yl)-3-(3-diethylaminopropyl)urea (30 mg, 0.11 mmol)was dissolved in ethoxyethanol (1.1 ml); pyridine hydrochloride (24 mg,0.22 mmol) and 5-aminoindole-1-carboxylic acid methylamide (22 mg, 0.12mmol, Production example 218-2) was added thereto; and the reactionmixture was stirred at 130° C. for 2 hours. After cooled down to roomtemperature, the reaction mixture was partitioned between a saturatedaqueous solution of sodium hydrogencarbonate and ethyl acetate; and theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia NH,hexane:ethyl acetate=1:3, ethyl acetate, ethyl acetate:methanol=93:7 inthis order) to yield the title compound (8 mg, 0.018 mmol, 17%) as paleyellow powder.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.94 (6H, t, J=6.8 Hz), 1.54 (2H, m),2.37-2.46 (6H, m), 2.83 (3H, d, J=3.6 Hz), 3.16 (2H, m), 6.42 (1H, d,J=5.8 Hz), 6.63 (1H, d, J=3.2 Hz), 6.73 (1H, s), 7.07 (1H, d, J=8.8 Hz),7.37 (1H, s), 7.76 (1H, d, J=5.8 Hz), 7.80 (1H, m), 8.08 (1H, m), 8.19(1H, d, J=8.8 Hz), 8.66 (1H, s), 8.81 (1H, m), 8.86 (1H, s).

ESI-MS: 438.36 (M+H).

The starting materials were synthesized as follows.

Production Example 199-1Phenyl(4-chloropyridin-2-yl)-N-(phenoxycarbonyl)carbamate

2-Amino-4-chloropyridine (5.00 g, 38.9 mmol, WO 02/32872) was dissolvedin tetrahydrofuran (200 ml); and triethylamine (17.9 ml, 128 mmol) wasadded thereto. While stirring with a waterbath, phenyl chloroformate(14.6 ml, 117 mmol) was added thereto dropwise; the reaction mixture wasstirred at room temperature for 1.5 hours. The reaction mixture waspartitioned between water and ethyl acetate; the organic layer waswashed with brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained residue was filtered by silica gel;the crystals obtained after the concentration were suspended in diethylether, filtered off, washed with diethyl ether, and dried to yield thetitle compound (3.77 g, 10.2 mmol, 26.3%) as pale yellow crystals. Themother liquor was concentrated under reduced pressure, which was thentreated by the similar methods to yield the title compound (3.98 g, 10.5mmol, 27.1%) as pale yellow crystals (secondary crystals).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.20 (4H, d, J=7.6 Hz), 7.30 (2H, t,J=7.6 Hz), 7.44 (4H, t, J=7.6 Hz), 7.68 (1H, dd, J=1.6, 5.2 Hz), 8.21(1H, d, J=1.6 Hz), 8.60 (1H, d, J=5.2 Hz).

Production Example 199-21-(4-Chloropyridin-2-yl)-3-(3-diethylaminopropyl)urea

Phenyl(4-chloropyridin-2-yl)-N-(phenoxycarbonyl)carbamate (738 mg, 2.00mmol) was dissolved in N,N-dimethylformamide (8.0 ml);N,N-diethyl-1,3-diaminopropane (1.57 ml, 10.0 mmol) was added thereto;and the reaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was partitioned between water and ethyl acetate; andthe organic layer was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia NH,hexane-ethyl acetate-methanol system) to yield the title compound (309mg, 1.09 mmol, 54.3%) as a pale brown oil.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (6H, t, J=7.0 Hz), 1.54 (2H, m),2.35-2.44 (6H, m), 3.16 (2H, m), 7.02 (1H, d, J=5.6 Hz), 7.54 (1H, s),7.73 (1H, brs), 8.13 (1H, d, J=5.6 Hz), 9.31 (1H, m).

Example 2005-(N-(2-(3-(3-Diethylaminopropyl)ureido)pyridin-4-yl)-N-methylamino)indole-1-carboxylicacid methylamide

Similarly to Example 199, the title compound (6 mg, 0.013 mmol, 12%) wasobtained as pale yellow powder from 5-(N-methylamino)indol-1-carboxylicacid methylamide (22 mg, 0.11 mmol),1-(4-chloropyridin-2-yl)-3-(3-diethylaminopropyl)urea (30 mg, 0.11 mmol,Production example 199-2) and pyridine hydrochloride (25 mg, 0.22 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.91 (6H, t, J=7.0 Hz), 1.51 (2H, m),2.34-2.43 (6H, m), 2.83 (3H, d, J=4.0 Hz), 3.13 (2H, m), 3.23 (3H, s),6.11 (1H, d, J=6.0 Hz), 6.40 (1H, s), 6.70 (1H, d, J=3.6 Hz), 7.10 (1H,d, J=8.6 Hz), 7.44 (1H, s), 7.69 (1H, d, J=6.0 Hz), 7.84 (1H, d, J=3.6Hz), 8.14 (1H, m), 8.27 (1H, d, J=8.6 Hz), 8.76 (1H, s), 8.78 (1H, brs).

ESI-MS: 452.38 (M+H).

The starting material was synthesized as follows.

Production Example 200-1 5-(N-Methylamino)indole-1-carboxylic acidmethylamide

5-Aminoindole-1-carboxylic acid methylamide (22 mg, 0.11 mmol,Production example 218-2) was dissolved in methanol (5.5 ml); andbenzotriazol-1-ylmethanol (434 mg, 2.91 mmol) was added thereto. Becausecrystals were precipitated immediately, methanol (5.5 ml) was added todissolve the precipitation, and the reaction mixture was stirred at roomtemperature for 1.25 hours. Then, the reaction mixture was heated andstirred at 60° C. for an hour. After cooled to room temperature,precipitated crystals were filtered off, washed by methanol, and driedto yield colorless crystals (421 mg). The crystals were dissolved in asolvent mixture of N,N-dimethylformamide (4.2 ml) and methanol (21 ml);sodium borohydride (99 mg, 2.63 mmol) was added while stirring at roomtemperature; and the reaction mixture was stirred for 1.5 hours. Sodiumborohydride (99 mg, 2.63 mmol) was further added thereto; and thereaction mixture was stirred at room temperature for 12 hours. A similarreaction was performed using the residue obtained by the concentrationof the mother liquor the crystals were previously given from underreduced pressure, and sodium borohydride (342 mg, 9.02 mmol). Bothreaction mixtures mentioned above were partitioned between a saturatedaqueous solution of sodium hydrogencarbonate and ethyl acetate; bothorganic layers are combined, washed with a saturated aqueous solution ofsodium hydrogencarbonate, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Fuji Silysia BW-300, hexane-ethylacetate-methanol system). The obtained crystals were suspended in ethylacetate, filtered off, washed with ethyl acetate, and dried to yield thetitle compound (255 mg, 1.25 mmol, 43.1%) was obtained as pale pinkcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.66 (3H, s), 2.78 (3H, d, J=4.4 Hz),5.32 (1H, brs), 6.42 (1H, d, J=3.6 Hz), 6.56 (1H, d, 2.4 Hz), 6.57 (1H,dd, J=2.4, 9.0 Hz), 7.61 (1H, d, J=3.6 Hz), 7.84 (1H, d, J=4.4 Hz), 7.93(1H, d, J=9.0 Hz).

Example 2015-(2-(3,3-Diethylureido)pyridin-4-ylamino)indole-1-carboxylic acidphenylamide

5-(2-Aminopyridin-4-ylamino)indole-1-carboxylic acid phenylamide (69 mg,0.20 mmol) was dissolved in tetrahydrofuran (14 ml); triethylamine(0.055 ml, 0.40 mmol) was added thereto; and phenyl chloroformate (0.038ml, 0.30 mmol) was added thereto while cooling with ice and stirring. Aportion of 7.0 ml of the reaction mixture was transferred to anothervessel and concentrated under reduced pressure. After the residue wasdissolved in N,N-dimethylformamide (1.0 ml), the similar reaction toExample 27 was performed by use of diethylamine (0.031 ml, 0.30 mmol).The obtained crude product was purified by TLC plate (Fuji Silysia NH,developing solvent: ethyl acetate) to yield the title compound (2.0 mg,0.005 mmol) as pale yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.07 (6H, t, J=7.0 Hz), 3.33 (4H, m),6.52 (1H, m), 6.72 (1H, m), 7.14 (2H, m), 7.40 (3H, m), 7.52 (1H, s),7.66 (2H, d, J=7.6 Hz), 7.83 (1H, d, J=6.4 Hz), 8.04 (1H, d, J=2.8 Hz),8.18 (2H, m), 8.65 (1H, s), 10.03 (1H, s).

ESI-MS: 443.28 (M+H).

The starting materials were synthesized as follows.

Production Example 201-1 5-Nitroindole-1-carboxilic acid phenylamide

Sodium hydride (802 mg, 20.0 mmol, 60% in oil) was suspended inN,N-dimethylformamide (40 ml); 5-nitroindole (2.50 g, 15.4 mmol) wasadded thereto; and the reaction mixture was stirred at room temperaturefor 30 minutes. Phenyl isocyanate (2.01 ml, 1.23 mmol) was addedthereto, and the reaction mixture was stirred at room temperature for1.5 hours. Water (80 ml) was added to the reaction mixture; the reactionmixture was stirred at room temperature for 30 minutes; and theprecipitated crystals were filtered off, washed by water and diethylether one by one, and dried by means F of suction to yield the titlecompound (3.53 g, 12.3 mmol, 79.8%) as pale yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.00 (1H, d, J=3.6 Hz), 7.16 (1H, t,J=8.0 Hz), 7.40 (2H, t, J=8.0 Hz), 7.65 (2H, d, J=8.0 Hz), 8.17 (1H, dd,J=2.4, 9.2 Hz), 8.25 (1H, d, J=3.6 Hz), 8.36 (1H, d, J=9.2 Hz), 8.62(1H, d, J=2.4 Hz), 10.30 (1H, s).

Production Example 201-2 5-Aminoindole-1-carboxylic acid phenylamide

5-Nitroindole-1-carboxylic acid phenylamide (3.53 g, 12.3 mmol) wasdissolved in ethanol (250 ml); water (50 ml), electrolytic iron powder(2.75 g, 49.2 mmol), ammonium chloride (5.26 g, 98.4 mmol) were addedthereto; and the reaction mixture was heated and stirred at 80° C. for 2hours. After cooling to room temperature, the reaction mixture wasfiltered off; insoluble portions were washed with ethyl acetate; and thefiltrate was concentrated under reduced pressure. The residue waspartitioned between water and a solvent mixture of ethyl acetate andtetrahydrofuran; and the organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was solidified by diethyl ether; the crystals were suspended indiethyl ether, filtered off, washed with diethyl ether, and dried toyield the title compound as pale red powder (681 mg, 2.71 mmol, 22.0%).The mother liquor was concentrated under reduced pressure, which wasthen treated by the similar methods to yield the title compound (590 mg,2.35 mmol, 19.1%) as pale red powder (secondary crystals).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.80 (2H, s), 6.48 (1H, d, J=3.4 Hz),6.59 (1H, dd, J=2.4, 8.8 Hz), 6.71 (1H, d, J=2.4 Hz), 7.09 (1H, t, J=7.6Hz), 7.34 (2H, t, J=7.6 Hz), 7.61 (2H, d, J=7.6 Hz), 7.84 (1H, d, J=3.4Hz), 7.88 (1H, d, J=8.8 Hz), 9.79 (1H, s).

Production Example 201-3 5-(2-Aminopyridin-4-ylamino)indole-1-carboxylicacid phenylamide

2-Amino-4-chloropyridine (500 mg, 0.446 mmol) was dissolved inN-methylpyrrolidone (5.0 ml); pyridine hydrochloride (750 mg) and5-aminoindole-1-carboxylic acid phenylamide (408 mg, 1.62 mmol) wasadded thereto; the reaction mixture was stirred at 100° C. for 6.5hours. After cooling to room temperature, the reaction mixture waspartitioned between saturated aqueous solution of sodiumhydrogencarbonate and ethyl acetate; the organic layer was washed withbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (Fuji Silysia NH, hexane-ethyl acetate-methanol system).The obtained pale yellow oil was solidified with diethyl ether; and thecrystals were suspended in diethyl ether, filtered off, washed withdiethyl ether, and dried to yield the title compound (188 mg, 0.464mmol, 35.7%) as pale yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.45 (2H, m), 5.99 (1H, d, J=2.0 Hz),6.10 (1H, dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 7.07 (1H, dd,J=2.0, 8.6 Hz), 7.12 (1H, t, J=7.6 Hz), 7.37 (3H, m), 7.56 (1H, d, J=6.0Hz), 7.63 (2H, d, J=7.6 Hz), 8.00 (1H, d, J=3.6 Hz), 8.14 (1H, d, J=8.6Hz), 8.26 (1H, s), 9.98 (1H, s).

Example 2025-(2-(3-(3-Diethylaminopropyl)ureido)pyridin-4-ylamino)indole-1-carboxylicacid phenylamide

5-(2-Aminopyridin-4-ylamino)indole-1-carboxylic acid phenylamide (69 mg,0.20 mmol, Production example 201-3) was dissolved in tetrahydrofuran(14 ml); triethylamine (0.055 ml, 0.40 mmol) was added thereto; andphenyl chloroformate (0.038 ml, 0.30 mmol) was added while stirring andcooled by ice. A portion of 7.0 ml of this reaction mixture wastransferred to another vessel; and the remaining portion of the reactionmixture was concentrated under reduced pressure. The residue wasdissolved in N,N-dimethylformamide (1.0 ml); the similar reaction toExample 201 was performed using N,N-diethyl-1,3-diaminopropane (0.047ml, 0.30 mmol); the crude product obtained was purified by a TLC plate(Fuji Silysia NH, developing solvent:ethyl acetate/ethanol=10/1); andthe obtained crystals were suspended in ethyl acetate, filtered off, anddried to yield the title compound (3 mg, 0.006 mmol) as colorlesscrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.0 Hz), 1.53 (2H, m),2.42 (6H, m), 3.18 (2H, m), 6.43 (1H, d, J=5.6 Hz), 6.70 (1H, s), 6.75(1H, s), 7.12 (2H, m), 7.38 (3H, m), 7.64 (2H, d, J=8.0 Hz), 7.76 (1H,d, J=5.6 Hz), 8.03 (1H, s), 8.16 (1H, d, J=9.2 Hz), 8.70 (1H, s), 8.78(1H, m), 8.86 (1H, s), 10.01 (1H, s).

ESI-MS: 500.54 (M+H).

Example 2035-(5-Cyano-2-(3-(2-diethylaminoethyl)ureido)pyridin-4-ylamino)indole-1-carboxylicacid phenylamide

A reaction similar to Production example 5-2 was performed using5-(2-amino-5-cyanopyridin-4-ylamino)indole-1-carboxylic acid phenylamide(60 mg, 0.16 mmol), triethylamine (0.056 ml, 0.41 mmol), and phenylchloroformate (0.082 ml, 0.66 mmol); the solvent was concentrated underreduced pressure. Similarly to Example 5, the title compound (63 mg,0.12 mmol, 76%) was obtained as pale yellow crystals from the residueobtained above, and 2-diethylaminoethylamine (0.115 ml, 0.81 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (6H, t, J=7.0 Hz), 2.38-2.46(6H, m), 3.09 (2H, m), 6.75 (1H, d, J=3.8 Hz), 7.03 (1H, brs), 7.13 (1H,dd, J=6.8, 7.6 Hz), 7.18 (1H, dd, J=2.0, 8.8 Hz), 7.38 (2H, t, J=7.6Hz), 7.48 (1H, d, J=2.0 Hz), 7.65 (3H, m), 8.07 (1H, d, J=3.8 Hz), 8.21(1H, d, J=8.8 Hz), 8.25 (1H, s), 8.87 (1H, s), 9.21 (1H, brs), 10.06(1H, s).

ESI-MS: 511.53 (M+H).

The starting material was synthesized as follows.

Production Example 203-15-(2-Amino-5-cyanopyridin-4-ylamino)indole-1-carboxylic acid phenylamide

2-Amino-4-chloro-5-cyanopyridine (200 mg, 1.30 mmol, Production example215-3) was dissolved in ethoxyethanol (13.0 ml);5-aminoindole-1-carboxylic acid phenylamide (408 mg, 1.62 mmol,Production example 201-2) and pyridine hydrochloride (315 mg, 2.73 mmol)were added thereto; and the reaction mixture was heated and stirred at130° C. for 4 hours. After cooling to room temperature, the reactionmixture was partitioned between a saturated aqueous solution of sodiumhydrogencarbonate and ethyl acetate; the organic layer was washed withbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (Fuji Silysia NH, hexane:ethyl acetate=2:3, ethylacetate, ethyl acetate:methanol=95:5 in this order). The pale yellow oilobtained was solidified with diethyl ether; the crystals were suspendedwith diethyl ether, filtered off, washed with diethyl ether, and driedto yield the title compound (171 mg, 0.464 mmol, 35.7%) as colorlesscrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.77 (1H, s), 6.40 (2H, brs), 6.74(1H, d, J=3.6 Hz), 7.13 (1H, t, J=7.6 Hz), 7.17 (1H, dd, J=2.4, 8.8 Hz),7.38 (2H, t, J=7.6 Hz), 7.46 (1H, d, J=2.4 Hz), 7.64 (2H, d, J=7.6 Hz),8.04 (1H, s), 8.05 (1H, d, J=3.6 Hz), 8.20 (1H, d, J=8.8 Hz), 8.35 (1H,s), 10.04 (1H, s).

Example 2045-(5-Cyano-2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-ylamino)indole-1-carboxylicacid phenylamide

Similarly to Example 203, the title compound (73 mg, 0.13 mmol, 82%) wasobtained as colorless crystals from5-(2-amino-5-cyanopyridin-4-ylamino)indole-1-carboxylic acid phenylamide(60 mg, 0.16 mmol, Production example 203-1), triethylamine (0.056 ml,0.41 mmol), phenyl chloroformate (0.082 ml, 0.66 mmol), and4-(pyrrolidin-1-yl)piperidine (126 mg, 0.81 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17-1.28 (2H, m), 1.62 (4H, m), 1.73(2H, m), 2.07 (1H, m), 2.42 (4H, m), 2.80 (2H, m), 3.87 (2H, m), 6.75(1H, d, J=3.6 Hz), 7.13 (1H, t, J=7.6 Hz), 7.18 (1H, d, J=8.8 Hz), 7.38(3H, m), 7.48 (1H, s), 7.64 (2H, d, J=7.6 Hz), 8.07 (1H, d, J=3.6 Hz),8.20 (1H, d, J=8.8 Hz), 8.30 (1H, s), 8.87 (1H, s), 9.20 (1H, brs),10.06 (1H, s).

ESI-MS: 549.48 (M+H).

Example 2055-(N-(2-(3-(3-Diethylaminopropyl)ureido)-5-cyanopyridin-4-yl)-N-methylamino)indole-1-carboxylicacid methylamide

Similarly to Example 203, the title compound (13 mg, 0.027 mmol, 67%)was obtained as colorless crystals from5-(N-(2-amino-5-cyanopyridin-4-yl)-N-methylamino)indole-1-carboxylicacid methylamide (13 mg, 0.041 mmol), phenyl chloroformate (0.011 ml,0.089 mmol), triethylamine (0.014 ml, 0.10 mmol), andN,N-diethyl-1,3-diaminopropane (0.032 ml, 0.21 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (6H, t, J=7.0 Hz), 1.53 (2H, m),2.41 (6H, m), 2.82 (3H, d, J=4.0 Hz), 3.14 (2H, m), 3.29 (3H, s), 6.65(1H, d, J=3.6 Hz), 7.09 (1H, s), 7.13 (1H, dd, J=2.0, 8.8 Hz), 7.45 (1H,d, J=2.0 Hz), 7.74 (1H, brs), 7.84 (1H, d, J=3.6 Hz), 8.10 (1H, s), 8.15(1H, m), 8.23 (1H, d, J=8.8 Hz), 9.27 (1H, s).

ESI-MS: 477.40 (M+H).

The starting material was synthesized as follows.

Production Example 205-15-(N-(2-Amino-5-cyanopyridin-4-yl)-N-methylamino) indole-1-carboxylicacid methylamide

Similarly to Production example 203, the title compound (13 mg, 0.041mmol, 35.7%) was obtained as colorless crystals from2-amino-4-chloro-5-cyanopyridine (27 mg, 0.18 mmol, Production example215-3), 5-(N-methylamino)indole-1-carboxylic acid methylamide (30 mg,0.15 mmol), and pyridine hydrochloride (38 mg, 0.38 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.77 (1H, s), 6.40 (2H, brs), 6.74(1H, d, J=3.6 Hz), 7.13 (1H, t, J=7.6 Hz), 7.17 (1H, dd, J=2.4, 8.8 Hz),7.38 (2H, t, J=7.6 Hz), 7.46 (1H, d, J=2.4 Hz), 7.64 (2H, d, J=7.6 Hz),8.04 (1H, s), 8.05 (1H, d, J=3.6 Hz), 8.20 (1H, d, J=8.8 Hz), 8.35 (1H,s), 10.04 (1H, s).

Example 206N1-Methyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Azetidine hydrochloride (104 mg, 1.11 mmol) and triethylamine (0.155 ml,1.11 mmol) were added to a dimethylformamide (1 ml) solution of phenylN-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(116 mg, 0.222 mmol) synthesized in Production example 5-2; and thereaction mixture was stirred overnight at room temperature. The reactionmixture was partitioned between ethyl acetate and water; the organiclayer was dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was washed with a solvent mixture ofether-hexane=1:1; and the resultant solid was filtered off to yield thetitle compound (50 mg) as crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.03-2.13 (2H, m), 2.83 (3H, d, J=6.2Hz), 3.99 (4H, t, J=7.9 Hz), 6.54 (1H, dd, J=2.2, 6.7 Hz), 6.68 (1H, d,J=3.9 Hz), 7.03 (1H, dd, J=2.2, 8.3 Hz), 7.35 (1H, d, J=2.2 Hz), 7.41(1H, d, J=2.2 Hz), 7.87 (1H, d, J=3.9 Hz), 8.04 (1H, d, J=6.7 Hz),8.03-8.20 (1H, m), 8.28 (1H, t, J=8.3 Hz), 8.88 (1H, s).

Example 207N1-Ethyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 206, the title compound (50 mg) was obtained aswhite crystals from phenylN-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate(120 mg, 0.224 mmol) synthesized in Production example 55-1,dimethylformamide (1 ml), azetidine hydrochloride (105 mg, 1.12 mmol),and triethylamine (0.156 ml, 1.12 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.19 (3H, t, J=7.9 Hz), 2.04-2.13(2H, m), 3.27-3.36 (2H, m), 3.90 (4H, t, J=7.0 Hz), 6.52 (1H, dd, J=1.9,6.5 Hz), 6.67 (1H, d, J=3.9 Hz), 7.02 (1H, dd, J=1.9, 8.4 Hz), 7.34 (1H,d, J=1.9 Hz), 7.42 (1H, d, J=1.9 Hz), 7.90 (1H, d, J=3.9 Hz), 8.05 (1H,d, J=6.5 Hz), 8.21 (1H, t, J=6.5 Hz), 8.28 1H, d, J=8.4 Hz), 8.88 (1H,s).

Example 208N1-Cyclopropyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Example 206, the title compound (80 mg) was obtained aswhite crystals from a mixture (228 mg) of phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamateand phenylN-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamateobtained by a similar method to Example 68, N,N-dimethylformamide (2ml), azetidine hydrochloride (194 mg, 2.07 mmol), and triethylamine(0.29 ml, 2.08 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.59-0.65 (2H, m), 0.70-0.78 (2H, m),2.03-2.13 (2H, m), 2.73-2.82 (1H, m), 3.89 (4H, t, J=7.1 Hz), 6.52 (1H,dd, J=2.0, 6.6 Hz), 6.64 (1H, d, J=3.9 Hz), 7.02 (1H, dd, J=2.0, 8.5Hz), 7.34 (1H, d, J=2.0 Hz), 7.41 (1H, d, J=2.0 Hz), 7.87 (1H, d, J=3.9Hz), 8.05 (1H, d, J=6.6 Hz), 8.23-8.30 (2H, m), 8.87 (1H, s).

Example 209N1-Methyl-5-(2-(((4-(morpholin-4-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Morpholine (228 mg, 1.64 mmol), sodium triacetoxyborohydride (372 mg,1.76 mmol), and acetic acid (0.134 ml, 2.34 mmol) were added to adichloromethane (3.5 ml) solution ofN1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide(476 mg) synthesized in Example 40, and stirred overnight at roomtemperature. The reaction mixture was partitioned between ethyl acetateand water; and the organic layer was dried over anhydrous sodiumsulfate. The solution was concentrated under reduced pressure; and theresidue was purified by silica gel column chromatography (Fuji SilysiaNH, ethyl acetate-methanol system). The resultant was washed with asolvent mixture of ether-hexane=1:1; and the solid was filtered off toyield the title compound (110 mg) as crystals.

MS Spectrum (ESI): 479 (M+1), 958 (2M+1).

Example 210N1-Methyl-5-(2-(((4-(azetidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Azetidine hydrochloride (179 mg, 2.00 mmol) and sodiumtriacetoxyborohydride (434 mg, 2.05 mmol) were added to adichloromethane (3.7 ml) solution ofN1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide(555 mg, 1.36 mmol) synthesized in Example 40, and stirred overnight atroom temperature. The reaction mixture was partitioned between ethylacetate and water; and the organic layer was dried over anhydrous sodiumsulfate. The solution was concentrated under reduced pressure; and theresidue was purified by use of silica gel column chromatography (FujiSilysia NH, ethyl acetate-methanol system). The resultant was washedwith a solvent mixture of ether-hexane=1:1; and the solid was filteredoff to yield crystals of the title compound (5 mg), and a mixture (410mg) including the title compound.

MS Spectrum (ESI): 449 (M+1), 897 (2M+1).

Example 211N1-Methyl-5-(2-(((4-(diethylamino)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Similarly to Example 209, the title compound (20 mg) was obtained ascrystals from a dichloromethane (4 ml) solution ofN1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarbox-amide(558 mg) synthesized in Example 40, diethylamine (0.199 ml, 1.92 mmol),sodium triacetoxyborohydride (436 mg, 2.06 mmol) and acetic acid (0.157ml, 2.74 mmol). A mixture (180 mg) including the title compound was alsoobtained.

MS Spectrum (ESI): 465 (M+1).

Example 212N1-Methyl-5-(2-(((4-(4-hydroxypiperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-1H-1-indolecarboxamide

Similarly to Example 209, the title compound (100 mg) was obtained ascrystals from a dichloromethane (3.5 ml) solution ofN1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)-amino-4-pyridyl)oxy-1H-1-indolecarboxamide(500 mg) synthesized in Example 40, 4-hydroxypiperidine (174 mg, 1.72mmol), sodium triacetoxyborohydride (389 mg, 1.84 mmol) and acetic acid(0.141 mg, 2.46 mmol).

MS Spectrum (ESI): 493 (M+1), 985(2M+1).

Example 213N1-Propyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

N1-Propyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (477 mg, 1.54mmol) was suspended in tetrahydrofuran (5 ml) at room temperature;triethylamine (0.536 mg, 3.08 mmol) and phenyl chloroformate (0.389 ml,3.85 mmol) was added thereto while stirring; and the reaction mixturewas stirred at room temperature for 2 hours. Water was added to thereaction mixture; this was subjected to extraction with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. N,N-dimethylformamide (3 ml) and pyrrolidine(0.27 ml, 3.23 mmol) was added to the residue; and the reaction mixturewas stirred at room temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water; and the organic layer wasdried over anhydrous sodium sulfate. The solution was concentrated underreduced pressure; the residue was purified by silica gel columnchromatography (Fuji Silysia NH, ethyl acetate-methanol). The resultantwas washed with a solvent mixture of ether:hexane=1:1; and the solid wasfiltered off to yield crystals (40 mg) of the title compound.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (3H, t, J=7.1 Hz), 1.52-1.65(2H, m), 1.74-1.82 (4H, m), 3.20-3.40 (6H, m), 6.56 (1H, dd, J=2.7, 6.3Hz), 6.68 (1H, d, J=3.6 Hz), 7.04 (1H, dd, J=2.7, 7.6 Hz), 7.37 (1H, d,J=2.7 Hz), 7.44 (1H, d, J=2.7 Hz), 7.94 (1H, d, J=3.6 Hz), 8.08 (1H, d,J=6.3 Hz), 8.23 (1H, t, J=7.1 Hz), 8.28 (1H, d, J=7.6 Hz), 8.61 (1H, s).

The starting materials were synthesized as follows.

Production Example 213-1N1-Propyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Sodium hydride (60% in oil, 104 mg, 2.6 mmol) was gradually added atroom temperature under nitrogen atmosphere to a N,N-dimethylformamide (7ml) solution of 4-(1H-5-indolyloxy)-2-pyridinamine (487 mg, 2.16 mmol,CAS No. 417722-11-3) which was described in WO 02/32872. After thereaction mixture was stirred for 2 hours, phenyl N-propylcarbamate (465mg, 2.6 mmol) was added thereto, and the reaction mixture was stirredfor 4 hours. The reaction mixture was partitioned between ethyl acetateand water; and the organic layer was washed with water and brine, driedover anhydrous sodium sulfate. The solution was concentrated underreduced pressure; and the residue was filtrated by silica gel columnchromatography (Fuji Silysia NH, ethyl acetate-methanol) to yield amixture (500 mg) including the title compound.

MS Spectrum (ESI): 311 (M+1).

Example 214N1-Isopropyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide

N1-Isopropyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (90 mg,0.29 mmol) was suspended in tetrahydrofuran (2 ml) at room temperature;triethylamine (0.121 mg, 0.868 mmol) and phenyl chloroformate (0.08 ml,0.633 mmol) was added thereto while stirring; and the reaction mixturewas stirred at room temperature for 2 hours. Water was added to thereaction mixture; this was subjected to extraction with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. N,N-Dimethylformamide (1 ml) and pyrrolidine(0.2 ml, 2.39 mmol) was added to the residue, and stirred at roomtemperature overnight. The reaction mixture was partitioned betweenethyl acetate and water; the organic layer was dried over anhydroussodium sulfate. This solution was concentrated under reduced pressure;and the residue was purified by silica gel column chromatography (FujiSilysia NH, ethyl acetate-methanol). The resultant was washed with asolvent mixture (ether:hexane=1:1); and the solid was filtered off toyield the title compound as crystals (65 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.23 (6H, d, J=6.8 Hz), 1.75-1.82(4H, m), 3.28-3.46 (4H, m), 3.98-4.09 (1H, m), 6.56 (1 h, dd, J=2.4, 6.0Hz), 6.68 (1H,d, J=3.6 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.37 (1H, d,J=2.4 Hz), 7.42 (1H, d, J=2.4 Hz), 7.84-8.00 (2H, m), 8.08 (1H, d, J=6.0Hz), 8.28 (1H, d, J=8.8 Hz), 8.61 (1H, s).

The starting materials were synthesized as follows.

Production Example 214-1N1-Isopropyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide

Similarly to Production example 213-1, the title compound was obtainedas crystals (220 mg) from 4-(1H-5-indolyloxy)-2-pyridinamine (482 mg,2.16 mmol, CAS No. 417722-11-3), which was described in WO 02/32872,N,N-dimethylformamide (7 ml), sodium hydride (60% in oil, 94 mg, 2.57mmol), and phenyl N-isopropylcarbamate (460 mg, 2.57 mmol) undernitrogen atmosphere.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.22 (6H, d, J=6.8 Hz), 3.97-4.08(1H, m), 5.76 (1H, d, J=2.0 Hz), 5.85 (2H, s), 6.14 (1H, dd, J=2.0, 5.6Hz), 6.67 (1H, d, J=3.6 Hz), 7.02 (1H, dd, J=2.0, 8.8 Hz), 7.34 (1H, d,J=2.4 Hz), 7.77 (1H, d, J=6.0 Hz), 7.94-7.96 (2H, m), 8.27 (1H, d, J=8.8Hz).

Example 215N1-Methyl-5-(2-(methylaminocarbonyl)amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamideProduction Example 215-1N1-Methyl-5-(2-amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide

6-Amino-4-(1H-5-indolyloxy)nicotinonitrile (63 mg, 0.252 mmol) wasdissolved in N,N-dimethylformamide (1 ml); and sodium hydride (60% inoil, 11.6 mg, 0.29 mmol) was gradually added thereto while stirring atroom temperature. After the reaction mixture was stirred for 30 minutes,phenyl N-propylcarbamate (49.5 mg, 0.277 mmol) was added thereto; andthe reaction mixture was stirred for 3 hours. A saturated aqueoussolution of ammonium chloride was added thereto; this was subjected toextraction with ethyl acetate, and dried over anhydrous sodium sulfate.This solution was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia NH, ethylacetate-methanol) to yield the title compound (12 mg) andN1-methyl-5-(2-amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide (17mg).

N1-Methyl-5-(2-(methylaminocarbonyl)amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.58 (3H, d, J=4.6 Hz), 2.86 (3H, d,J=4.6 Hz), 7.15 (1H, dd, J=2.0, 8.3 Hz), 7.20-7.28 (1H, m), 7.51 (1H, d,J=2.0 Hz), 7.93 (1H, d, J=3.0 Hz), 8.22 (1H, q, J=4.6 Hz), 8.34 (3H, d,J=8.3 Hz), 8.59 (1H, s), 9.51 (1H, s).

N1-Methyl-5-(2-amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.85 (3H, d, J=4.9 Hz), 5.59 (1H, s),6.72 (1H, d, J=2.6 Hz), 6.87 (2H, brs), 7.13 (1H, dd, J=1.6, 8.5 Hz),7.49 (1H, d, J=1.6 Hz), 7.92 (1H, d, J=2.6 Hz), 8.21 (1H, q, J=4.9 Hz),8.28 (1H, s), 8.34 (1H, d, J=8.5 Hz).

Production Example 215-2 2-Amino-4-chloro-5-iodopyridine

N,N-Dimethylformamide (47 ml) and N-iodosuccinimide (10.7 g, 47.6 mmol)were added to 2-amino-4-chloropyridine (4.72 g, 36.7 mmol); and thereaction mixture was stirred overnight. An aqueous solution of sodiumthiosulfate and ethyl acetate were added thereto; the organic layer wasseparated, concentrated, and dried over anhydrous sodium sulfate. Thiswas concentrated under reduced pressure; a solvent mixture(ether:hexane=1:1) was added to the residue; and the solid was filteredoff to yield the title compound (7.0 g, 27.5 mmol).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.56 (2H, brs), 6.68 (1H,s), 8.32 (1H,s).

Production example 215-3 2-Amino-4-chloro-5-cyanopyridine

1-Methyl-2-pyrrolidone (20 ml), zinc cyanide (0.49 g, 4.17 mmol) andtetrakis(triphenylphosphine)palladium (1.3 g, 1.12 mmol) were added to2-amino-4-chloro-5-iodopyridine (1.93 g, 7.58 mmol) synthesized inProduction example 215-2; and the reaction mixture was stirred at130-135° C. for 5 hours. Approximately 0.28% of aqueous ammonium (100ml) and ethyl acetate was added to the reaction mixture; and the organiclayer was separated, washed with brine, and dried over anhydrous sodiumsulfate. This was concentrated under reduced pressure and the residuewas filtrated by silica gel column chromatography (Fuji Silysia NH,ethyl acetate). After concentration under reduced pressure, a solventmixture (ether:hexane=1:1) was added to the residue, and stirred; andthe solid was filtered off to yield the title compound as crystals (680mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.03 (2H, brs), 6.58 (1H,s), 8.32 (1H,s).

MS Spectrum (EI): 153 (M).

Production Example 215-4 6-Amino-4-(1H-5-indolyloxy)nicotinonitrile

5-Hydroxyindole (313 mg, 2.35 mmol) was dissolved in dimethyl sulfoxide(3 ml); and sodium hydride (90 mg, 2.25 mmol) was gradually addedthereto while stirring at room temperature. After the reaction mixturewas stirred for 1 hour, 2-amino-4-chloro-5-cyanopyridine (300 mg, 1.96mmol) synthesized in Production example 215-3 was added thereto; and thereaction mixture was heated and stirred at 120° C. for 4 hours. Afterallowing to be cooled to room temperature, the reaction mixture waspartitioned between ethyl acetate and water; and the organic layer waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was distilled off; the residue was subjected to silica gelcolumn chromatography (Fuji Silysia NH, ethyl acetate-methanol);fractions containing the desired compound was concentrated under reducedpressure; ether was added thereto; and the solid was filtered off, anddried under reduced pressure to yield the title compound (95 mg, 0.38mmol, 59%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.59 (1H, s), 6.48 (1H, s), 6.82 (2H,s), 6.92 (1H, dd, J=2.0, 9.0 Hz), 7.40 (1H, d, J=2.0 Hz), 7.46 (1H, t,J=2.0 Hz), 7.50 (1H, d, J=9.0 Hz), 8.26 (1H, s), 11.30 (1H, s).

Example 216N1-Methyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide

N1-Methyl-5-(2-amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide (20mg) synthesized in Example 215 was suspended in tetrahydrofuran (0.5 ml)at room temperature; triethylamine (0.121 ml, 0.868 mmol) and phenylchloroformate (0.08 ml, 0.633 mmol) was added thereto while stirring;and the reaction mixture was stirred at room temperature for 2 hours.Water was added to the reaction mixture; this was subjected toextraction with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure.N,N-Dimethylformamide and pyrrolidine (0.013 ml) was added to a portionof the residue (14 mg); and the reaction mixture was stirred overnight.The reaction mixture was partitioned between ethyl acetate and water;and the organic layer was dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Fuji Silysia NH, ethyl acetate-methanol). Theresultant was washed with a solvent mixture (ether:hexane=1:1) to yieldthe title compound as crystals (6 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.74 (4H, brs), 2.85 (3H, d, J=4.4Hz), 3.15-3.40 (4H, m), 6.72 (1H, d, J=4.7 Hz), 7.15 (1H, dd, J=1.9, 8.4Hz), 7.37 (1H, s), 7.50 (1H, d, J=1.9 Hz), 7.93 (1H, d, J=4.7 Hz),8.20-8.26 (1H, m), 8.33 (1H, d, J=8.4 Hz), 8.63 (1H, s), 9.28 (1H, brs).

Example 217N1-Methyl-5-(2-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide

N1-Methyl-5-(2-amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide (15mg, 0.049 mmol) synthesized in Example 215 was suspended intetrahydrofuran (0.5 ml) at room temperature; triethylamine (17 μl,0.122 mmol) and phenyl chloroformate (14 μl, 0.072 mmol) was addedthereto while stirring; and the reaction mixture was stirred at roomtemperature for 2 hours. Water was added to the reaction mixture, thiswas subjected to extraction with ethyl acetate, washed with brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.N,N-Dimethylformamide (0.5 ml) and 4-(1-pyrrolidinyl)piperidine (28 mg,0.18 mmol) was added to a portion of the residue (14 mg); and thereaction mixture was stirred at room temperature overnight. The reactionmixture was partitioned between ethyl acetate and water; and the organiclayer was dried over anhydrous sodium sulfate. This was concentratedunder reduced pressure; and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, ethyl acetate-methanol). Theresultant was washed with a solvent mixture (ether:hexane=1:1); and thesolid was filtered off to yield the title compound as crystals (6 mg).

MS Spectrum (ESI): 488 (M+1), 975 (2M+1).

Example 218N1-Methyl-5-(2-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino-5-cyano-4-pyridyl)amino-1H-1-indolecarboxamide

N1-Methyl-5-(2-amino-5-cyano-4-pyridyl)amino-1H-1-indolecarboxamide (50mg, 0.16 mmol) was suspended in tetrahydrofuran (1 ml) at roomtemperature; triethylamine (0.057 ml, 0.41 mmol) and phenylchloroformate (0.041 ml, 0.325 mmol) was added thereto while stirring;and the reaction mixture was stirred at room temperature for 2 hours.Water was added to the reaction mixture; this was subjected toextraction with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure.N,N-Dimethylformamide (0.5 ml) and 4-(1-pyrrolidinyl)piperidine (100 mg,0.648 mmol) was added to the residue; and the reaction mixture wasstirred at room temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water; and the organic layer wasdried over anhydrous sodium sulfate. This was concentrated under reducedpressure; and the residue was purified by silica gel columnchromatography (Fuji Silysia NH, ethyl acetate-methanol) to yield thetitle compound (65 mg, 0.134 mmol).

MS Spectrum (ESI): 487 (M+1).

The starting materials were synthesized as follows.

Production Example 218-1 N1-Methyl-5-nitro-1H-1-indolecarboxamide

Sodium hydride (60% in oil, 228 mg, 5.7 mmol) was gradually added to aN,N-dimethylformamide (0.5 ml) solution of 5-nitroindole (0.841 g, 5.19mmol) while stirring at room temperature; phenyl N-methylcarbamate (1.02g, 6.74 mmol) was added thereto; and the reaction mixture was stirredovernight. The reaction mixture was partitioned between ethyl acetateand water; and the organic layer was washed with water and brine, driedover anhydrous sodium sulfate. This was concentrated under reducedpressure; and the residue was purified by silica gel columnchromatography (hexane-ethyl acetate, sequentially ethyl acetate) toyield the title compound (600 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.88 (3H, d, J=4.4 Hz), 6.94 (1H, d,J=3.6 Hz), 8.03 (1H, d, J=3.6 Hz), 8.15 (1H, dd, J=2.4, 9.2 Hz),8.35-8.43 (2H, m), 8.59 (1H, d, J=2.4 Hz).

Production Example 218-2 N1-Methyl-5-amino-1H-1-indolecarboxamide

Methanol (6 ml), water (2 ml), iron (0.32 g) and ammonium chloride (0.64g) were added to N1-methyl-5-nitro-1H-1-indolecarboxamide (0.32 g, 1.46mmol) synthesized in Production example 218-1; and the reaction mixturewas heated to reflux for 2 hours. The reaction mixture was partitionedbetween ethyl acetate and water; the organic layer was washed with waterand brine, and dried over anhydrous sodium sulfate. The residue wasfiltrated with celite, and concentrated under reduced pressure to yieldthe title compound (210 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.79 (3H, d, J=4.4 Hz), 4.73 (2H,brs), 6.48 (1H, d, J=3.6 Hz), 6.56 (1H, dd, J=2.4, 8.8 Hz), 6.68 (1H, d,J=1.6 Hz), 7.60 (1H, d, J=3.6 Hz), 7.80-7.88 (1H, m), 7.89 (1H, d, J=8.8Hz).

Production Example 218-3N1-Methyl-5-(2-amino-5-cyano-4-pyridyl)amino-1H-1-indolecarboxamide

2-Amino-4-chloro-5-cyanopyridine (123 mg, 0.80 mmol) synthesized inProduction example 215-3, ethoxyethanol (3 ml) and pyridinehydrochloride (186 mg, 1.60 mmol) were added toN1-methyl-5-amino-1H-1-indolecarboxamide (198 mg, 1.05 mmol) synthesizedin Production example 218-2; and the reaction mixture was stirred at130° C. for 3 hours. After allowing to be cooled to room temperature,the reaction mixture was partitioned between a saturated aqueoussolution of sodium hydrogencarbonate and ethyl acetate; and the organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate. The solvent was distilled off, and the residue was purified bysilica gel column chromatography (hexane-ethyl acetate, ethyl acetate inthis order) to yield the title compound (110 mg, 0.359 mmol).

MS Spectrum (ESI): 307 (M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.84 (3H, d, J=4.4 Hz), 5.75 (1H, s),6.39 (2H, s), 6.66 (1H, d, J=3.2 Hz), 7.13 (1H, dd, J=2.0, 8.8 Hz), 7.42(1H, d, J=2.0 Hz), 7.82 (1H, d, J=3.2 Hz), 8.04 (1H, s), 8.08-8.14 (1H,m), 8.23 (1H, d, J=8.8 Hz), 8.30 (1H, s).

Example 219N1-Methyl-5-(2-(3-(2-diethylaminoethyl)ureido)amino-5-cyano-4-pyridyl)amino-1H-1-indolecarboxamide

N1-Methyl-5-(2-amino-5-cyano-4-pyridyl)amino-1H-1-indolecarboxamide (36mg, 0.12 mmol) synthesized in Production example 218-3 was suspended intetrahydrofuran (2 ml) at room temperature; triethylamine (0.1 ml, 0.72mmol) and phenyl chloroformate (0.037 ml, 0.29 mmol) were added theretowhile stirring; and the reaction mixture was stirred at room temperaturefor 2 hours. Water was added to the reaction mixture; this was subjectedto extraction with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure.N,N-Dimethylformamide (0.5 ml) and N,N-diethylaminoethylamine (0.1 ml)were added to the residue; and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was partitioned betweenethyl acetate and water; the organic layer was washed with brine, driedover anhydrous sodium sulfate. This was concentrated under reducedpressure; and the residue was purified by silica gel columnchromatography (Fuji Silysia NH, ethyl acetate-methanol) to yield thetitle compound (25 mg, 0.056 mmol).

MS Spectrum (ESI): 449 (M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm) 0.93 (6H, t, J=6.8 Hz), 2.37-2.50 (6H,m), 2.84 (3H, d, J=4.4 Hz), 3.10 (2H, q, J=6.8 Hz), 6.68 (1H, d, J=3.2Hz), 7.05 (1H, s), 7.15 (1H, dd, J=2.4, 8.8 Hz), 7.44 (1H, d, J=3.2 Hz),7.70 (1H, brs), 7.84 (1H, d, J=4.0 Hz), 8.14 (1H, d, J=4.4 Hz), 8.24(1H, d, J=8.8 Hz), 8.25 (1H, s), 8.84 (1H, s), 9.21 (1H, s).

Example 220N1-Diethyl-2-methyl-5-(2-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)amino-5-cyano-4-pyridyl)amino-1H-1-indolecarboxamide

N1-Diethyl-2-methyl-5-(2-amino-5-cyano-4-pyridyl)amino-1H-1-indolecarboxamide(84 mg, 0.249 mmol) was suspended in tetrahydrofuran (1 ml) at roomtemperature; triethylamine (0.2 ml, 1.43 mmol) and phenyl chloroformate(0.079 ml, 0.626 mmol) were added thereto while stirring; and thereaction mixture was stirred at room temperature for 2 hours. Water wasadded to the reaction mixture; and this was subjected to extraction withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. N,N-Dimethylformamide (0.5 ml)and 4-(1-pyrrolidinyl)piperidine (173 mg, 0.111 mmol) was added to aportion (80 mg) of the obtained residue (120 mg), and the reactionmixture was stirred at room temperature overnight. The reaction mixturewas partitioned between ethyl acetate and water; and the organic layerwas dried over anhydrous sodium sulfate. This was concentrated underreduced pressure; and the residue was purified by silica gel columnchromatography (Fuji Silysia NH, ethyl acetate-methanol system) to yieldthe title compound (45 mg, 0.083 mmol).

MS Spectrum (ESI):543.5 (M+1).

The starting materials were synthesized as follows.

Production Example 220-1N1-Diethyl-2-methyl-5-nitro-1H-1-indolecarboxamide

Sodium hydride (60% in oil, 94 mg) was gradually added to aN,N-dimethylformamide (0.5 ml) solution of 2-methyl-5-nitroindole (0.841g, 5.19 mmol) while stirring at room temperature; diethylcarbamoylchloride (0.341 ml) was added thereto; and the reaction mixture washeated and stirred at 70° C. for 4 hours. After cooling down to roomtemperature, the reaction mixture was partitioned between ethyl acetateand water; the organic layer was washed with water and brine, and driedover anhydrous sodium sulfate. This was concentrated under reducedpressure; and the residue was purified by silica gel columnchromatography (Fuji Silysia NH; hexane-ethyl acetate, ethyl acetate inthis order) to yield the title compound (420 mg).

MS Spectrum (ESI): 330 (M+55).

Production Example 220-2N1-Diethyl-2-methyl-5-amino-1H-1-indolecarboxamide

Methanol (8 ml), water (2 ml), iron powder (0.42 g) and ammoniumchloride (0.84 g) were added to N1-methyl-5-nitro-1H-1-indolecarboxamide(415 g, 1.46 mmol) synthesized in Production example 220-1; and thereaction mixture was heated to reflux for 2 hours. The reaction mixturewas partitioned between ethyl acetate and water; and the organic layerwas washed with water and brine, and dried over anhydrous sodiumsulfate. The filtration with celite, and concentration under reducedpressure yield the title compound (322 mg).

MS Spectrum (ESI): 246 (M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.10 (6H, t, J=7.2 Hz), 2.28 (3H, s),3.25-3.40 (4H, m), 4.92 (2H, brs), 6.10 (1H, t, J=0.8 Hz), 6.51 (1H, dd,J=2.4, 8.4 Hz), 6.64 (1H, d, J=2.4 Hz), 6.89 (1H, d, J=8.4 Hz).

Production Example 220-3N1-Diethyl-2-methyl-5-(2-amino-5-cyano-4-pyridyl)amino-1H-1-indolecarboxamide

2-Amino-4-chloro-5-cyanopyridine (140 mg, 0.92 mmol) synthesized inProduction example 215-3, ethoxyethanol (2.5 ml), and pyridinehydrochloride (223 mg, 1.92 mmol) was added toN1-diethyl-2-methyl-5-amino-1H-1-indolecarboxamide (320 mg, 1.31 mmol)synthesized in Production example 220-2; and the reaction mixture wasstirred at 130° C. for 3 hours. After cooling down to room temperature,the reaction mixture was partitioned between a saturated aqueoussolution of sodium hydrogencarbonate and ethyl acetate; and the organiclayer was washed with water and brine, and dried over anhydrous sodiumsulfate. The solvent was distilled off; and the residue was purified bysilica gel column chromatography (hexane-ethyl acetate, sequentiallyethyl acetate) to yield the title compound (110 mg, 0.359 mmol).

MS Spectrum (ESI): 363 (M+1).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.05-1.20 (6H, m), 2.36 (3H, s),3.25-3.40 (4H, m), 5.68 (1H, s), 6.35-6.37 (3H, m), 7.02 (1H, dd, J=2.0,8,4 Hz), 7.19 (1H, d, J=8.4 Hz), 7.30 (1H, d, J=2.0 Hz), 8.01 (1H, s),8.22 (1H, s).

Example 2215-(5-Iodo-2-(3-methylureido)pyrimidin-4-yloxy)-1H-indole-1-carboxylicacid methylamide

PhenylN-(5-iodo-4-(1-methylaminocarbonyl-1H-indol-5-yloxy)pyrimidin-2-yl)-N-(phenoxycarbonyl)carbamate(597 mg, 0.919 mmol) was dissolved in dimethylformamide (3.0 ml); a 40%methanol solution of methylamine (1.0 ml) was added while stirring at 0°C.; and the reaction mixture was further stirred for 30 minutes keepingthe temperature. Water (10 ml) was added to the reaction mixture afterthe completion of the reaction; the precipitated crystals were filteredoff, washed with water, methanol and diethyl ether, and dried under warmaeration to yield the title compound as white crystals (367 mg, 0.787mmol, 86%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.04 (3H, D, J=4.8 Hz), 2.85 (3H, d,J=4.0 Hz), 6.73 (1H, d, J=3.6 Hz), 7.16 (1H, dd, J=2.4, 8.8 Hz), 7.52(1H, d, J=2.4 Hz), 7.61 (1H, m), 7.92 (1H, d, J=3.6 Hz), 8.20 (1H, m),8.35 (1H, d, J=8.8 Hz), 8.69(1H, s), 9.78 (1H, brs).

The starting materials were synthesized as follows.

Production Example 221-1N1-Methyl-5-(2-amino-4-pyrimidyl)oxy-1H-1-indolecarboxamide

Similarly to Production example 1-3, the title compound was obtained aswhite powder from 4-(1H-5-indolyloxy)-2-pyrimidinamine (413 mg, 1.83mmol) synthesized in Production example 1-2 and phenyl N-methylcarbamate(332 mg, 2.20 mmol) synthesized in Production example 2-1.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.84 (3H, d, J=4.0 Hz), 6.06 (1H, d,J=5.6 Hz), 6.57 (2H, brs), 6.67 (1H, d, J=3.6 Hz), 7.04 (1H, dd, J=2.4,8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.85 (1H, d, J=3.6 Hz), 8.08 (1H, d,J=5.6 Hz), 8.14 (1H, m), 8.25 (1H, d, J=8.8 Hz).

Production Example 221-2N1-Methyl-5-(2-amino-5-iodo-4-pyrimidyl)oxy-1H-1-indolecarboxamide

N1-Methyl-5-(2-amino-4-pyrimidyl)oxy-1H-1-indolecarboxamide (302 mg,1.07 mmol) and N-iodosuccinimide (301 mg, 1.34 mmol) were dissolved inN,N-dimethylformamide (3.0 ml); and the reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was partitionedbetween ethyl acetate and water; and the organic layer was washed withwater and brine, and was dried over anhydrous magnesium sulfate. Thesolvent was distilled off; and the residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate:hexane=2:1) to yield thetitle compound as yellow crystals (224 mg, 0.547 mmol, 51%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.84 (3H, d, J=4.4 Hz), 6.67 (1H, d,J=3.6 Hz), 6.72 (2H, brs), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d,J=2.4 Hz), 7.85 (1H, d, J=3.6 Hz), 8.15 (1H, m), 8.24 (1H, d, J=8.8 Hz),8.33 (1H, s).

Production Example 221-3 PhenylN-(5-iodo-4-(1-methylaminocarbonyl-1H-indol-5-yloxy)pyrimidin-2-yl)-N-(phenoxycarbonyl)carbamate

N1-Methyl-5-(2-amino-5-iodo-4-pyrimidyl)oxy-1H-1-indolecarboxamide (205mg, 0.500 mmol) was suspended in tetrahydrofuran (5.0 ml); triethylamine(0.209 ml, 1.50 mmol) was added thereto while stirring. The suspensionwas cooled with ice; phenyl chloroformate (0.188 ml, 1.50 mmol) wasadded thereto; and the reaction mixture was stirred at room temperaturefor 3 hours. The reaction mixture was partitioned between ethyl acetateand a saturated aqueous solution of sodium hydrogencarbonate; and theorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and brine, and was dried over anhydrous magnesiumsulfate. After solvent distillation, the obtained crude product wascrystallized from ethyl acetate-hexane; and the crystals were filteredoff, and dried under aeration to yield the title compound as whitecrystals (207 mg, 0.319 mmol, 64%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.09 (3H, d, J=4.8 Hz), 5.56 (1H, m),6.56 (1H, d, J=3.6 Hz), 6.98-7.14 (4H, m), 7.17-7.34 (6H, m), 7.36-7.42(2H, m), 7.68 (1H, s), 8.12 (1H, d, J=8.8 Hz), 8.74 (1H, s).

Example 222N1-Cyclopropyl-5-((2-(((2-chloroethylamino)carbonyl)amino)-4-pyridyl)oxy)-1H-1-indolecarboxamide

N1-cyclopropyl-5-((2-amino-4-pyridyl)oxy)-1H-1-indolecarboxamide (400mg, CAS No. 417722-12-4) described in WO02/32872, 2-chloroethylisocyanate (150 mg) and tetrahydrofuran (5 ml) were stirred at 80° C.for 1.5 hours. The mixture was cooled to room temperature, silica gelwas added, and the solvent was distilled off under reduced pressure. Thesilica gel was charged into a dry column packed with silica gel, andpurification was performed by column chromatography (hexane:ethylacetate=1:1, followed by ethyl acetate) to yield 280 mg of a colorlesspowder.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H, m),2.73-2.80 (1H, m), 3.42 (2H, q, J=6.0 Hz), 3.61 (2H, t, J=6.0 Hz), 6.52(1H, dd, J=5.6 Hz, 2.4 Hz), 6.65 (1H, d, J=3.6 Hz), 6.85 (1H, d, J=2.4Hz), 7.04 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.86 (1H,d, J=3.6 Hz), 8.04 (1H, d, J=5.6 Hz), 8.27 (1H, s), 8.28 (1H, d, J=8.8Hz), 8.34 (1H, brs), 9.19 (1H, s).

The structural formulas of the compounds obtained in Production examplesand Examples above are shown in Tables 5 to 17 below.

TABLE 5

TABLE 6

TABLE 7

TABLE 8

TABLE 9

TABLE 10

TABLE 11

TABLE 12

TABLE 13

TABLE 14

TABLE 15 EXAMPLE 152

EXAMPLE 153

EXAMPLE 154

EXAMPLE 155

EXAMPLE 156

EXAMPLE 157

EXAMPLE 158

EXAMPLE 159

EXAMPLE 160

EXAMPLE 161

EXAMPLE 162

EXAMPLE 163

EXAMPLE 164

EXAMPLE 165

EXAMPLE 166

EXAMPLE 167

EXAMPLE 168

EXAMPLE 169

EXAMPLE 170

TABLE 16 EXAMPLE 171

EXAMPLE 172

EXAMPLE 173

EXAMPLE 174

EXAMPLE 175

EXAMPLE 176

EXAMPLE 177

EXAMPLE 178

EXAMPLE 179

EXAMPLE 180

EXAMPLE 181

EXAMPLE 182

EXAMPLE 183

EXAMPLE 184

EXAMPLE 185

EXAMPLE 186

EXAMPLE 187

EXAMPLE 188

EXAMPLE 189

EXAMPLE 190

EXAMPLE 191

EXAMPLE 192

EXAMPLE 193

EXAMPLE 194

EXAMPLE 195

EXAMPLE 196

EXAMPLE 197

EXAMPLE 198

EXAMPLE 199

EXAMPLE 200

EXAMPLE 201

EXAMPLE 202

EXAMPLE 203

EXAMPLE 204

EXAMPLE 205

TABLE 17 EXAMPLE 206

EXAMPLE 207

EXAMPLE 208

EXAMPLE 209

EXAMPLE 210

EXAMPLE 211

EXAMPLE 212

EXAMPLE 213

EXAMPLE 214

EXAMPLE 215

EXAMPLE 216

EXAMPLE 217

EXAMPLE 218

EXAMPLE 219

EXAMPLE 220

EXAMPLE 221

EXAMPLE 222

According to the present invention, it is possible to provide novelcompounds that exhibit (1) powerful inhibitory action against tubeformation by vascular endothelial cells induced by VEGF or FGF and (2)powerful inhibitory action against receptor kinases for VEGF or FGF, andwhich are highly useful as medicines.

It should be noted that the tube formation by vascular endothelial cellsis an important process in angiogenesis, and compounds having inhibitoryaction against them therefore has angiogenesis-inhibiting action. Inaddition, it is known that angiogenesis in the body progresses by theadditive/synergistic effect of a multiple angiogenic factors representedby VEGF and FGF (Koolwijk P, van Erck M G M, de Vree W J A, Vermeer M A,Weich H A, Hance maaijer R, van Hinsbergh V W M,. Cooperative effect ofTNF-alpha, bFGF and VEGF on the formation of tubular structures of humanmicrovascular endothelial cells in a fibrin matrix. Role of urokinaseactivity. J. Cell Biol., 132 P. 1177-1188, (1996)).

Therefore, the compounds of the invention which inhibit tube formationinduced by VEGF or FGF produced by cancer cells and the like areexpected to exhibit powerful angiogenesis inhibition in vivo, and shouldbe highly useful as angiogenesis inhibitors. Moreover, the compounds ofthe invention are highly useful as angiogenesis inhibitors, and are alsouseful as prophylactic or therapeutic agents for diseases for whichangiogenesis inhibition is effective, angiogenesis inhibitors, antitumoragents, therapeutic agents for angioma, cancer metastasis inhibitors,therapeutic agents for retinal neovascularization, therapeutic agentsfor diabetic retinopathy, therapeutic agents for inflammatory disease,therapeutic agents for inflammatory disease selected from deformantarthritis, rheumatoid arthritis, psoriasis or delayed hypersensitivityreaction, therapeutic agents for atherosclerosis, and angiogenesisinhibition-based antitumor agents.

In addition, when using the compounds of the invention as antitumoragents, the tumors include, for example, a pancreatic cancer, a gastriccancer, a colon cancer, a breast cancer, a prostate cancer, a lungcancer, a renal cancer, a brain tumor, a blood cancer and an ovariancancer; and the tumors to be suitably targeted are a gastric cancer, acolon cancer, a prostate cancer or a renal cancer.

1. A compound represented by the general formula:

or a salt or hydrate thereof, wherein: X₁ represents a group representedby the formula —CR₁₀═; X₂ represents a group represented by the formula—CR₁₁═; Y represents an oxygen atom, a sulfur atom, a sulfinyl group, asulfonyl group, or a group represented by the formula —NR_(Y)— (whereinR_(Y) represents a hydrogen atom or a C₁₋₆ alkyl group); R₁ representsan optionally substituted C₁₋₆ alkoxy group, an optionally substitutedC₆₋₁₀ aryloxy group, a group represented by the formula—NR_(12a)R_(12b), a group represented by formula (VIII):

(wherein Y_(A1) and Y_(A2) each independently represents a grouprepresented by the formula -A₁₀-A₁₁-A₁₂ (wherein A₁₀ represents a singlebond or an optionally substituted C1-6 alkylene; A₁₁ represents a singlebond, an oxygen atom, a carbonyl group or a sulfonyl group; and A₁₂represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a 5- to10-membered heteroaryl group, a group represented by the formula—NR_(A10)R_(A11), a group represented by the formula —OR_(A12) (whereinR_(A10), R_(A11) and R_(A12) each independently represents a hydrogenatom, a C1-6 alkyl group or C₃₋₈ cycloalkyl group) or a grouprepresented by the formula:

(wherein e represents 1 or 2; Z represents an oxygen atom, a grouprepresented by the formula —CR_(X7)R_(X8)— or a group represented by theformula —NR_(X9)—; R_(X7), R_(X8) and R_(X9) each independentlyrepresents a hydrogen atom, a hydroxyl group or a C₁₋₆ alkyl group));and Y_(A3) represents a hydrogen atom or an optionally substituted C₁₋₆alkyl group) or a group represented by the formula:

(wherein T1 represents an optionally substituted 5- to 10-memberedaromatic heterocycle which may have X in the ring or an optionallysubstituted 3- to 10-membered heterocycle which may have X in the ring);R₂, R₃, R₄, R₅, R₆ and R₈ each represents a hydrogen atom; R₇ representsa halogen atom, a cyano group, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈cycloalkyl group, a group represented by the formula —CO—R₁₃, a grouprepresented by the formula —NR₁₄—CO—R₁₃, a group represented by theformula —SO₂—R₁₅, a group represented by the formula —NR₁₄—SO₂—R₁₅, or agroup represented by the formula —NR_(16a)R_(16b); R₁₀ and R₁₁ eachindependently represents a hydrogen atom, a halogen atom, a cyano group,an optionally substituted C₁₋₆ alkyl group, an optionally substitutedC₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynyl group, anoptionally substituted C₃₋₈ cycloalkyl group, a group represented by theformula —CO—R₁₃, a group represented by the formula —NR₁₄—CO—R₁₃, agroup represented by the formula —SO₂—R₁₅, a group represented by theformula —NR₁₄—SO₂—R₁₅, or a group represented by the formula—NR_(16a)R_(16b); R₉ represents a group represented by the formula—NR_(16a)R_(16b); R_(12a) and R_(12b) each independently represents ahydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₃₋₆ alkenyl group, an optionally substituted C₃₋₆ alkynylgroup, an optionally substituted C₃₋₈ cycloalkyl group, an optionallysubstituted 3- to 10-membered heterocyclic group, or an optionallysubstituted C₁₋₆ alkoxy group; R₁₃ represents a hydrogen atom, anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆alkenyl group, an optionally substituted C₂₋₆ alkynyl group, anoptionally substituted C₃₋₈ cycloalkyl group, an optionally substitutedC₆₋₁₀ aryl group, an optionally substituted 5- to 10-membered heteroarylgroup, an optionally substituted 3- to 10-membered heterocyclic group,an optionally substituted C₁₋₆ alkoxy group, an optionally substitutedC₆₋₁₀ aryloxy group, a group represented by the formula—NR_(12a)R_(12b), or a group represented by the formula:

(wherein T2 represents an optionally substituted 5- to 10-memberedaromatic heterocycle or an optionally substituted 3- to 10-memberedheterocycle); R₁₄ represents a hydrogen atom, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedC₃₋₈ cycloalkyl group, or a group represented by the formula —CO—R₁₃;R₁₅ represents an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted C₃₋₈ cycloalkyl group, an optionallysubstituted C₆₋₁₀ aryl group, an optionally substituted 5- to10-membered heteroaryl group, or an optionally substituted 3- to10-membered heterocyclic group; R_(16a) and R_(16b) each independentlyrepresents a hydrogen atom, an optionally substituted C₁₋₆ alkyl group,an optionally substituted C₃₋₆ alkenyl group, an optionally substitutedC₃₋₆ alkynyl group, an optionally substituted C₃₋₈ cycloalkyl group, anoptionally substituted C₆₋₁₀ aryl group or an optionally substitutedC₁₋₆ alkoxy group; and X represents an oxygen atom, a sulfur atom, acarbonyl group, a sulfonyl group, a group represented by the formula—CR_(X1)R_(X2)—, or a group represented by the formula —NR_(X3)—(wherein R_(X1), R_(X2) and R_(X3) each independently represents ahydrogen atom or a group represented by the formula -A₁-A₂-A₃ (whereinA₁ and A₂ each independently represents a single bond, an optionallysubstituted C₁₋₆ alkylene group or a carbonyl group; and A₃ represents ahydrogen atom, a C₃₋₈ cycloalkyl group, a group represented by theformula —NR_(A1)R_(A2), or the formula —OR_(A3) (wherein, R_(A1), R_(A2)and R_(A3) each independently represents a hydrogen atom or a C₁₋₆ alkylgroup), or an optionally substituted group represented by the formula:

(wherein a represents 1 or 2))).
 2. A compound represented by thegeneral formula:

or a salt or hydrate thereof, wherein: X₁ represents a group representedby the formula —CR₁₀═; X₂ represents a group represented by the formula—CR₁₁═; Y represents an oxygen atom, a sulfur atom, a sulfinyl group, asulfonyl group, or a group represented by the formula —NR_(Y)— (whereinR_(Y) represents a hydrogen atom or a C₁₋₆ alkyl group); R₁ representsan optionally substituted C₁₋₆ alkoxy group, an optionally substitutedC₆₋₁₀ aryloxy group, a group represented by the formula—NR_(12a)R_(12b), a group represented by formula (VIII):

(wherein Y_(A1) and Y_(A2) each independently represents a grouprepresented by the formula -A₁₀-A₁₁-A₁₂ (wherein A₁₀ represents a singlebond or an optionally substituted C1-6 alkylene; A₁₁ represents a singlebond, an oxygen atom, a carbonyl group or a sulfonyl group; and A₁₂represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ aryl group, a 5- to10-membered heteroaryl group, a group represented by the formula—NR_(A10)R_(A11), a group represented by the formula —OR_(A12) (whereinR_(A10), R_(A11) and R_(A12) each independently represents a hydrogenatom, a C1-6 alkyl group or C₃₋₈ cycloalkyl group) or a grouprepresented by the formula:

(wherein e represents 1 or 2; Z represents an oxygen atom, a grouprepresented by the formula —CR_(X7)R_(X8)— or a group represented by theformula —NR_(X9)—; R_(X7), R_(X8) and R_(X9) each independentlyrepresents a hydrogen atom, a hydroxyl group or a C₁₋₆ alkyl group));and Y_(A3) represents a hydrogen atom or an optionally substituted C₁₋₆alkyl group) or a group represented by the formula:

(wherein T1 represents an optionally substituted 5- to 10-memberedaromatic heterocycle which may have X in the ring or an optionallysubstituted 3- to 10-membered heterocycle which may have X in the ring);R₂, R₃, R₄, R₅, R₆ and R₈ each represents a hydrogen atom; R₇ representsa halogen atom, a cyano group, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈cycloalkyl group, a group represented by the formula —CO—R₁₃, a grouprepresented by the formula —NR₁₄—CO—R₁₃, a group represented by theformula —SO₂—R₁₅, a group represented by the formula —NR₁₄—SO₂—R₁₅, or agroup represented by the formula —NR_(16a)R_(16b); R₁₀ and R₁₁ eachindependently represents a hydrogen atom, a halogen atom, a cyano group,an optionally substituted C₁₋₆ alkyl group, an optionally substitutedC₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynyl group, anoptionally substituted C₃₋₈ cycloalkyl group, a group represented by theformula —CO—R₁₃, a group represented by the formula —NR₁₄—CO—R₁₃, agroup represented by the formula —SO₂—R₁₅, a group represented by theformula —NR₁₄—SO₂—R₁₅, or a group represented by the formula—NR_(16a)R_(16b); R₉ represents a group represented by the formula—NR_(16a)R_(16b); R_(12a) and R_(12b) each independently represents ahydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₃₋₆ alkenyl group, an optionally substituted C₃₋₆ alkynylgroup, an optionally substituted C₃₋₈ cycloalkyl group, an optionallysubstituted 3- to 10-membered heterocyclic group, or an optionallysubstituted C₁₋₆ alkoxy group; R₁₃ represents a hydrogen atom, anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆alkenyl group, an optionally substituted C₂₋₆ alkynyl group, anoptionally substituted C₃₋₈ cycloalkyl group, an optionally substitutedC₆₋₁₀ aryl group, an optionally substituted 5- to 10-membered heteroarylgroup, an optionally substituted 3- to 10-membered heterocyclic group,an optionally substituted C₁₋₆ alkoxy group, an optionally substitutedC₆₋₁₀ aryloxy group, a group represented by the formula—NR_(12a)R_(12b), or a group represented by the formula:

(wherein T2 represents an optionally substituted 5- to 10-memberedaromatic heterocycle or an optionally substituted 3- to 10-memberedheterocycle); R₁₄ represents a hydrogen atom, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedC₃₋₈ cycloalkyl group, or a group represented by the formula —CO—R₁₃;R₁₅ represents an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted C₃₋₈ cycloalkyl group, an optionallysubstituted C₆₋₁₀ aryl group, an optionally substituted 5- to10-membered heteroaryl group, or an optionally substituted 3- to10-membered heterocyclic group; R_(16a) and R_(16b) each independentlyrepresents a hydrogen atom, an optionally substituted C₁₋₆ alkyl group,an optionally substituted C₃₋₆ alkenyl group, an optionally substitutedC₃₋₆ alkynyl group, an optionally substituted C₃₋₈ cycloalkyl group, anoptionally substituted C₆₋₁₀ aryl group or an optionally substitutedC₁₋₆ alkoxy group; and X represents an oxygen atom, a sulfur atom, acarbonyl group, a sulfonyl group, a group represented by the formula—CR_(X1)R_(X2)—, or a group represented by the formula —NR_(X3)—(wherein R_(X1), R_(X2) and R_(X3) each independently represents ahydrogen atom or a group represented by the formula -A₁-A₂-A₃ (whereinA₁ and A₂ each independently represents a single bond, an optionallysubstituted C₁₋₆ alkylene group or a carbonyl group; and A₃ represents ahydrogen atom, a C₃₋₈ cycloalkyl group, a group represented by theformula —NR_(A1)R_(A2), or the formula —OR_(A3) (wherein, R_(A1), R_(A2)and R_(A3) each independently represents a hydrogen atom or a C₁₋₆ alkylgroup), or an optionally substituted group represented by the formula:

(wherein a represents 1 or 2))).
 3. A compound according to claim 1 or2, wherein Y represents an oxygen atom, a group represented by theformula —NH—, or a group represented by the formula —N(CH₃)—.
 4. Acompound according to claim 1 or 2, wherein Y represents an oxygen atom.5. A compound according to claim 1 or 2, wherein both X₁ and X₂represent —CH═.
 6. A compound according to claim 1 or 2, wherein R₇represents a halogen atom or an optionally substituted C₁₋₆ alkyl group.7. A compound according to claim 1 or 2, wherein R₉ represents a grouprepresented by the formula —NHR₁₇, wherein R₁₇ represents an optionallysubstituted C₁₋₆ alkyl group, a C₃₋₆ alkynyl group, a C₃₋₈ cycloalkylgroup or an optionally substituted C₆₋₁₀ aryl group.
 8. A compoundaccording to claim 1 or 2, wherein R₉ represents a group represented bythe formula —NR_(18a)R_(18b), wherein R_(18a) and R_(18b) eachindependently represents a C₁₋₆ alkyl group.
 9. A compound according toclaim 1 or 2, wherein R₉ represents a group represented by the formula—NHR₁₉, wherein R₁₉ represents a C₁₋₆ alkyl group, a C₃₋₆ alkynyl group,a C₃₋₈ cycloalkyl group or a C₆₋₁₀ aryl group.
 10. A compound accordingto claim 1 or 2, wherein R₉ represents a group represented by theformula —NHR₂₀, wherein R₂₀ represents a methyl group, an ethyl group ora cyclopropyl group.
 11. A compound according to claim 1 or 2, whereinR₉ represents a group represented by the formula —NH(CH₃).
 12. Acompound according to claim 1 or 2, wherein R₁ represents a furtheroptionally substituted group represented by formula (III′):

(wherein b₂ represents 0, 1 or 2; and X represents an oxygen atom, asulfur atom, a carbonyl group, a sulfonyl group, a group represented bythe formula —CR_(X1)R_(X2)—, or a group represented by the formula—NR_(X3)— (wherein R_(X1), R_(X2) and R_(X3) each independentlyrepresents a hydrogen atom or a group represented by the formula-A₁-A₂-A₃ (wherein A₁ and A₂ each independently represents a singlebond, an optionally substituted C₁₋₆ alkylene group or a carbonyl group;and A₃ represents a hydrogen atom, a C₃₋₈ cycloalkyl group, a grouprepresented by the formula —NR_(A1)R_(A2), or the formula —OR_(A3)(wherein, R_(A1), R_(A2) and R_(A3) each independently represents ahydrogen atom or a C₁₋₆ alkyl group), or an optionally substituted grouprepresented by the formula:

(wherein a represents 1 or 2))).
 13. A compound according to claim 1 or2, wherein R₁ represents a group represented by formula (IV):

(wherein X represents an oxygen atom, a sulfur atom, a carbonyl group, asulfonyl group, a group represented by the formula —CR_(X1)R_(X2)—, or agroup represented by the formula —NR_(X3)— (wherein R_(X1), R_(X2) andR_(X3) each independently represents a hydrogen atom or a grouprepresented by the formula -A₁-A₂-A₃ (wherein A₁ and A₂ eachindependently represents a single bond, an optionally substituted C₁₋₆alkylene group or a carbonyl group; and A₃ represents a hydrogen atom, aC₃₋₈ cycloalkyl group, a group represented by the formula—NR_(A1)R_(A2), or the formula —OR_(A3) (wherein, R_(A1), R_(A2) andR_(A3) each independently represents a hydrogen atom or a C₁₋₆ alkylgroup), or an optionally substituted group represented by the formula:

(wherein a represents 1 or 2))).
 14. A compound according to claim 13,wherein X in formula (IV) represents an oxygen atom.
 15. A compoundaccording to claim 13, wherein X in formula (IV) represents a grouprepresented by formula (V):

(wherein R_(X4) represents a hydrogen atom or a group represented by theformula -A₄-A₅-A₆ (wherein A₄ and A₅ each independently represents asingle bond, an optionally substituted C₁₋₆ alkylene or a carbonylgroup; and A₆ represents a hydrogen atom, a C₃₋₈ cycloalkyl group or agroup represented by the formula —NR_(A4)R_(A5) or the formula —OR_(A6)(wherein R_(A4), R_(A5) and R_(A6) each independently represents ahydrogen atom or a C₁₋₆ alkyl group))).
 16. A compound according toclaim 13, wherein X in formula (IV) represents a group represented byformula (VI):

(wherein R_(X5) and R_(X6) each independently represents a hydrogen atomor a group represented by the formula -A₇-A₈-A₉ (wherein A₇ and A₈ eachindependently represents a single bond, an optionally substituted C₁₋₆alkylene group or a carbonyl group; and A₉ represents a hydrogen atom, aC₃₋₈ cycloalkyl group, a group represented by the formula—NR_(A7)R_(A8), or the formula —OR_(A9) (wherein R_(A7), R_(A8), andR_(A9) each independently represents a hydrogen atom or a C₁₋₆ alkylgroup), or a group represented by the formula:

(wherein c₁ represents 0, 1 or 2))).
 17. A compound according to claim16, wherein one of R_(X5) and R_(X6) in the formula (VI) represents ahydroxyl group and the other represents a hydrogen atom or a C₁₋₆ alkylgroup.
 18. A compound according to claim 16, wherein one of R_(X5) orR_(X6) in the formula (VI) represents a hydrogen atom and the otherrepresents a group represented by the formula:

(wherein c₂ represents 1 or 2).
 19. A compound according to claim 1 or 2wherein R₁ represents a group represented by formula (VII):

(wherein R_(X51) and R_(X61) each independently represents a hydrogenatom or a group represented by the formula -A₇₁-A₈₁-A₉₁ (wherein A₇₁ andA₈₁ each independently represents a single bond, an optionallysubstituted C₁₋₆ alkylene group or a carbonyl group; and A₉₁ representsa hydrogen atom, a C₃₋₈ cycloalkyl group, a group represented by theformula —NR_(A71)R_(A81), or the formula —OR_(A91) (wherein R_(A71),R_(A81), and R_(A91) each independently represents a hydrogen atom or aC₁₋₆ alkyl group), or a group represented by the formula:

(wherein c₁₁ represents 0, 1 or 2))).
 20. A compound according to claim1 or 2, wherein R₁ represents a group represented by formula (VIII):

(wherein Y_(A1) and Y_(A2) each independently represents a grouprepresented by the formula -A₁₀-A₁₁-A₁₂ (wherein A₁₀ represents a singlebond or an optionally substituted C₁₋₆ alkylene group; A₁₁ represents asingle bond, an oxygen atom, a carbonyl group, or a sulfonyl group; andA₁₂ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₀ arylgroup, a 5- to 10-membered heteroaryl group, a group represented by theformula —NR_(A10)R_(A11), or the formula —OR_(A12) (wherein, R_(A10),R_(A11), and R_(A12) each independently represents a hydrogen atom, aC₁₋₆ alkyl group or a C₃₋₈ cycloalkyl group), or a group represented bythe formula:

(wherein e represents 1 or 2; and Z represents an oxygen atom or a grouprepresented by the formula —CR_(X7)R_(X8)— or the formula —NR_(X9)—(wherein R_(X7), R_(X8) and R_(X9) each independently represents ahydrogen atom, a hydroxyl group or a C₁₋₆ alkyl group))); and Y_(A3)represents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup).
 21. A compound according to claim 20, wherein one of Y_(A1) andY_(A2) in the formula (VIII) represents a hydrogen atom and the otherrepresents a group represented by the formula —(CH₂)₂-A₁₃-A₁₄ (whereinA₁₃ represents a single bond, a carbonyl group or a sulfonyl group; andA₁₄ represents a C₁₋₆ alkyl group, a group represented by the formula—NR_(A13)R_(A14) (wherein R_(A13) and R_(A14) each independentlyrepresents a hydrogen atom, a C₁₋₆ alkyl group or a C₃₋₈ cycloalkylgroup), or a group represented by the formula:

(wherein e represents 1 or 2; and Z represents an oxygen atom or a grouprepresented by the formula —CR_(X7)R_(X8)— or the formula —NR_(X9)—(wherein R_(X7), R_(X8) and R_(X9) each independently represents ahydrogen atom, a hydroxyl group or a C₁₋₆ alkyl group))); and Y_(A3) informula (VIII) represents a hydrogen atom.
 22. A compound according toclaim 1 or 2, wherein R₁ represents a group selected from:

(wherein, each of the foregoing members being optionally substitutedwith a group selected from Substituent Group Alpha, wherein SubstituentGroup Alpha is a group consisting of a halogen atom, a hydroxyl group, athiol group, a nitro group, a cyano group, a carboxyl group, an aminogroup, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, and a group selectedfrom:

(wherein R_(N1) and R_(N2) each independently represents a hydrogen atomor a C₁₋₆ alkyl group)).
 23. A compound according to claim 1 or 2,wherein R₁ represents a group selected from:


24. A compound according to claim 1 or 2, wherein R₁ represents a groupselected from:


25. A compound according to claim 1 or 2, wherein R₁ represents a groupselected from:


26. A compound according to claim 1, wherein the compound is selectedfrom the group consisting of (102)N1-methyl-3-chloro-5-(2-(((3-(diethylamino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(103)N1-methyl-3-chloro-5-(2-((4-(pyrrolidin-1-yl)piperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(104)N1-methyl-3-chloro-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(105)N1-methyl-3-chloro-5-(2-(((3-(4-hydroxypiperidino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(106)N1-methyl-3-chloro-5-(2-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(107)N4-(4-(3-chloro-1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide;(108)N1-methyl-3-chloro-5-(2-((4-(ethylpiperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(109)N1-ethyl-3-chloro-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(110)N1-ethyl-3-chloro-5-(2-(((3-(4-hydroxypiperidino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(111)N1-ethyl-3-chloro-5-(2-(((3-(diethylamino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(112)N1,3-dimethyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(113)N1,3-dimethyl-5-(2-((4-(pyrrolidin-1-yl)piperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide;(114)N1-cylopropyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-3-methyl-1H-1-indolecarboxamide;and (115)N1-cylopropyl-5-(2-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-3-methyl-1H-1-indolecarboxamide.27. A compound according to claim 1, wherein the compound is (25)N1-methyl-3-chloro-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide.